Glucosylceramide synthase inhibitors for the treatment of diseases

ABSTRACT

Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority of U.S.Provisional Application No. 61/880,752, filed Sep. 20, 2013, the contentof which is hereby incorporated by reference in its entirety.

FIELD

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments containing such compounds,and methods of using such compounds to treat or prevent diseases orconditions associated with the enzyme glucosylceramide synthase (GCS).

BACKGROUND

Glucosylceramide synthase (GCS) is a key enzyme which catalyzes theinitial glycosylation step in the biosynthesis of glucosylceramide-basedglycosphingolipids (GSLs) namely via the transfer of glucose fromUDP-glucose (UDP-Glc) to ceramide to form glucosylceramide. GCS is atransmembrane, type III integral protein localized in the cis/medialgolgi. Glycosphingolipids (GSLs) are believed to be integral in manycell membrane events, including cellular interactions, signaling, andtrafficking. Synthesis of GSL structures has been shown (Proc. Natl.Acad. Sci USA 1999, 96(16), 9142-9147) to be essential for embryonicdevelopment and for the differentiation of some tissues. Ceramide playsa central role in sphingolipid metabolism, and downregulation of GCSactivity has been shown to have marked effects on the sphingolipidpattern with diminished expression of glycosphingolipids. Sphingolipidshave a role in physiological as well as pathological cardiovascularconditions. In particular, sphingolipids and their regulating enzymesappear to play a role in adaptive responses to chronic hypoxia in theneonatal rat heart (Prostaglandins & Other Lipid Mediators 2005,78(1-4), 249-263).

GCS inhibitors have been proposed for the treatment of a variety ofdiseases (see, for example, WO2005068426). Such diseases includeglycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GM1gangliosidosis and Fabry diseases), diseases associated with glycolipidaccumulation (e.g., Gaucher disease), diseases that cause renalhypertrophy or hyperplasia such as diabetic nephropathy, diseases thatcause hyperglycemia or hyperinsulinemia, cancers in which glycolipidsynthesis is abnormal, infectious diseases caused by organisms which usecell surface glycolipids as receptors, infectious diseases in whichsynthesis of glucosylceramide is essential or important, diseases inwhich excessive glycolipid synthesis occurs (e.g., atherosclerosis,polycystic kidney disease, and renal hypertrophy), neuronal disorders,neuronal injury, inflammatory diseases or disorders associated withmacrophage recruitment and activation (e.g., rheumatoid arthritis,Crohn's disease, asthma and sepsis), pain (see WO2008011483—neuropathicpain, inflammatory pain, headache pain, somatic pain, visceral pain,referred pain), cognitive disorders (see WO2008/109286—agnosia; amnesia;aphasia; an apraxia; delirium; dementia including AIDS dementia complex,Binswanger's disease, dementia with Lewy Bodies, frontotemporaldementia, mild cognitive impairment, multi-infarct dementia, Pick'sdisease, semantic dementia, senile dementia, and vascular dementia; andlearning disorders including Asperger's syndrome, attention deficitdisorder, attention deficit hyperactivity disorder, autism, childhooddisintegrative disorder, and Rett syndrome), neurodegenerative disorders(such as Alzheimer's disease, corticobasal degeneration,Creutzfeldt-Jacob disease, frontotemporal lobar degeneration, Huntingtondisease, multiple sclerosis, normal pressure hydrocephalus, organicchronic brain syndrome, Parkinson's disease, Pick disease, progressivesupranuclear palsy, and senile dementia (Alzheimer type), glomerulardisease, and diabetes mellitus and obesity (see WO 2006053043). Renalhypertrophy induced by diabetes is associated with enhanced synthesis ofglycosphingolipids such as glucosylceramide and ganglioside GM3 whichaccumulate in the kidney of rats (J. Clin. Invest. 1993, 91(3), 797).

It has been shown that overexpression of GCS is implicated in multi-drugresistance and disrupts ceramide-induced apoptosis. For example,Turzanski et al. (Experimental Hematology 2005, 33(1), 62-72) have shownthat ceramide induces apoptosis in acute myeloid leukemia (AML) cellsand that P-glycoprotein (p-gp) confers resistance to ceramide-inducedapoptosis, with modulation of the ceramide-glucosylceramide pathwaymaking a marked contribution to this resistance in TF-I cells. Thus, GCSinhibitors can be useful for treatment of proliferative disorders (suchas cancer) by inducing apoptosis in diseased cells.

Sandhoff (or type 2 GM2 gangliosidosis) is caused by a deficiency in(3-hexosaminidase A and B activity which leads to an accumulation of theganglioside GM2 and other glycolipids causing damage to the centralnervous system and eventually is lethal (PLoS One 2011, 6(6), e21758).Tay-Sachs disease (or GM2 gangliosidosis) is caused by a deficiency in(1-hexosaminidase A which lead to an accumulation of gangliosides in thebrain's nerve cells eventually leading to their premature death.Intravenous injection of the missing enzyme(s) is not a viable option asof the enzymes does cross the blood-brain barrier (Genetics in Medicine2009, 1(6), 425). Glucosylceramide synthase is a key enzyme in thesynthesis of glucosylceramide and other glycosphingolipids. Itsinhibition can decrease the amount of the glycosphingolipids whichaccumulate in Sandhoff disease.

Fabry disease is caused by loss of activity of the lysosomal hydrolaseα-galactosidase which leads to an accumulation of glycosphingolipids(particularly globotriaosylceramide) causing pain, renal disease andfailure, cerebral vascular disease, and myocardial infarction (KidneyInternational 2000, 57, 446). One treatment strategy is to provide thedefective enzyme to the patient; however, enzyme replacement therapy canonly slow the progression of the disease and is not a cure. Analternative or complementary strategy is one where glucosylceramidesynthase, a key enzyme in the synthesis of glycosphingolipids, isinhibited with a small molecule thus decreasing the amount ofglobotriaosylceramide and other glucosylceramide-based lipids that needto be broken down by hydrolase α-galactosidase.

Gaucher disease is caused by a defect in the enzyme lysosomalglucocerebrosidase which is responsible for catalyzing the breakdown ofglucosylceramide which then accumulates in tissues of affected people(J. Org. Chem. 2007, 72(4), 1088) causing liver malfunction, skeletaldisorders, painful bone lesions, hypersplenism, pancytopenia, andneurological symptoms (convulsions, hypertonia, mental retardation,apnea, dementia, and ocular muscle apraxia). One treatment strategy isto provide the defective enzyme to the patient; however, enzymereplacement therapy is not suitable for all patients and does notaddress the neurological manifestations of the disease for those withtype 2 and type 3. An alternative or complementary strategy is one whereglucosylceramide synthase is inhibited with small molecules thusdecreasing the amount of glucosylceramide that needs to be broken downby glucocerebrosidase.

Nonalcoholic fatty liver disease (NALD) is a disease where fataccumulates in the liver of people who drink little or no alcohol andresults in inflammation and scarring of the liver which can progress toliver failure. Inhibition of glucosylceramide synthase in ob/ob micelowered glucose levels, lowered liver/body weight ratio, decreased theaccumulation of triglycerides, and prevented and reversed steatosis(Hepatology 2009, 50(1), 85-93). Thus GCS inhibitors are useful for theprevention and treatment of NALD.

Polycystic kidney disease (PKD) is a genetic disease characterized bynoncancerous cysts which are filled with fluid and cause the kidneys toenlarge which can result in a decrease in quality of life (e.g.,headaches, high blood pressure, back and side pain, colon problems,mitral valve prolapsed, and kidney stones) and can be life-threatening(e.g. kidney failure, aneurysm in the brain, and high blood pressurewhich can lead to heart disease and stroke). PKD can also damage theliver, spleen, pancreas, vasculature, testes, seminal vesicles, andintestines. Glucosylceramide and ganglioside GM3 levels in the kidneyare higher than in normal tissue (Nat Med 2010, 16(7), 788). Thus,blocking the synthesis of glucosylceramide with an inhibitor of GCS canbe useful in the treatment of PKD to reduce new cyst formation (partialor complete inhibition of cystogenesis), reduce cyst mass, reduce thesize and number of cysts, and/or reduce the severity of the symptomsassociated. All current treatments for PKD address symptoms and do nottreat the underlying cause of the disease (Nat Med 2010, 16(7), 788).

SUMMARY OF THE INVENTION

In one aspect, provided is a compound of Formula I:

where

-   R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);-   X¹ is alkylene, alkenylene, or cycloalkylene;-   R^(1a) is alkyl, heterocycloalkyl, aryl or heteroaryl each of which    is optionally substituted with 1, 2, or 3 R⁷ groups;-   R² and R³ together with the nitrogen to which they are attached form    a 3-10 membered heterocycloalkyl ring, optionally substituted with    1, 2, 3, 4, 5, 6, 7, or 8 R⁸;-   R⁴ is aryl or heteroaryl each of which is optionally substituted    with 1, 2, 3, or 4 R⁹ groups;-   R⁵ is —OH, and R^(5a) is hydrogen;-   R⁶ and R^(6a) are halo; R⁶ and R^(6a) are deuterium; or R⁶ and    R^(6a) together with the carbon to which they are attached form    C(═NOH) or C(O);-   each R⁷, when present, is independently nitro, cyano, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl,    heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl,    heteroarylalkyl, or heteroaryloxy; where the phenyl and the    heteroaryl, either alone or as part of another group, are    independently optionally substituted with 1, 2 or 3 R^(7a);-   each R^(7a), when present, is independently selected from cyano,    halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;-   each R⁸, when present, is independently deuterium, amino,    alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl,    or cycloalkyl; or two R⁸ together with the carbon to which they are    attached form C(O);-   each R⁹, when present, is independently cyano, nitro, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy,    alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio,    cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl,    heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the    heterocycloalkyl and the phenyl, either alone or as part of another    group, are independently optionally substituted with 1 or 2 R^(9a);-   each R^(9a), when present, is independently selected from alkyl,    hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino,    alkylamino, and dialkylamino; and-   R¹² is hydrogen or C₁₋₅ alkyl; optionally a tautomer, a single    stereoisomer or mixture of stereoisomers thereof and additionally    optionally a pharmaceutically acceptable salt thereof.

In a further aspect, provided is a pharmaceutical compositioncomprising 1) a compound of Formula I optionally as a tautomer, a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof, and 2) apharmaceutically acceptable excipient or pharmaceutically acceptablecarrier.

In a further aspect, provided is a method of treating a disease ordisorder comprising administering a compound of Formula I, optionally asa tautomer, a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof, or the pharmaceutical composition thereof additionallycomprising a pharmaceutically acceptable excipient or pharmaceuticallyacceptable carrier.

In a further aspect, it is provided a method of making a compound ofFormula I, comprising

-   -   a) treating an intermediate of formula 100

-   -   or a salt thereof, where R², R³, R⁴, and all other groups are as        defined in the Summary of the Invention or as in any of the        embodiments described herein; with an intermediate of formula        R¹C(O)OH using standard amide coupling conditions to yield a        Compound of Formula I where R⁵ is hydroxy and R^(5a) is hydrogen        and R¹ is as defined in the Summary of the Invention or as in        any of the embodiments described herein; and    -   b) optionally separating individual isomers.

DETAILED DESCRIPTION Abbreviations

Abbreviation Meaning ACN acetonitrile aq aqueous Boc tert-butoxycarbonylCBz conc concentrated DAST diethylaminosulfur trifluoride DIPEAdiisoproylethylamine DCM dichlorormethane DIBAL diisobutylaluminumhydride DMF dimethylformamide DMP Dess-Martin periodinane DMSO dimethylsulfoxide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide h hoursHATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HOBt hydroxybenzotriazole mg milligram mHz megahertzmL milliliter μL microliter Ms mesyl NBS N-bromosuccinimide NMR nuclearmagnetic resonance PE petroleum ether rt or RT room temperature satsaturated TBAF tetra-n-butylammonium fluoride TBDMStert-butyldimethylsilyl TBS tert-butyl-silyl TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below. Generally, the nomenclature used herein andthe laboratory procedures in organic chemistry, medicinal chemistry, andpharmacology described herein are those well-known and commonly employedin the art. Unless defined otherwise, all technical and scientific termsused herein generally have the same meaning as commonly understood byone of ordinary skill in the art to which this disclosure belongs.

As used throughout this application and the appended claims, thefollowing terms have the following meanings:

“About” preceding a numerical value refers to a range of values ±10% ofthe value specified.

“Acceptable” with respect to a formulation, composition or ingredient,as used herein, means having no persistent detrimental effect on thegeneral health of the subject being treated.

“Alkoxy” means an —OR group where R is alkyl, as defined herein. In someembodiments, alkoxy includes, but are not limited to, methoxy, ethoxy,propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

“Alkoxycarbonyl” means a —C(O)R group where R is alkoxy, as definedherein.

“Alkenyl” means a straight or branched hydrocarbon radical having from 2to 8 carbon atoms and at least one double bond. “Lower alkenyl” means analkenyl group having one to six carbon atoms. In some embodiments,alkenyl includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl,1-hex-5-enyl and the like.

“Alkenylene” means a divalent alkenyl group, as defined herein.

“Alkenyloxy” means an —OR group where R is alkenyl, as defined herein.

“Alkyl” means a straight or branched saturated hydrocarbon radicalcontaining from 1-10 carbon atoms, in another example 1-6 carbon atoms.In some embodiments, alkyl includes, but is not limited to, methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein, oran N-oxide derivative thereof. In some embodiments, alkylamino includesmethylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino,or methylamino-N-oxide, and the like.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Alkylaminocarbonyl” means a —C(O)NHR group where R is alkyl, as definedherein.

“Alkylene” means a divalent alkyl group, as defined herein.

“Alkynyl” means a straight or branched hydrocarbon radical having from 2to 8 carbon atoms and at least one triple bond.

“Amino” means —NH₂.

“Aminoalkyl” means an alkyl group substituted with at least one, forexample one, two, or three, amino groups.

“Aminocarbonyl” means a —C(O)NH₂ group.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. In someembodiments, the examples of aryl include phenyl, naphthyl, and indanyl,and the like.

“Carboxy” means a —C(O)OH group.

“Cycloalkyl” means a monocyclic or fused bicyclic, saturated orpartially unsaturated (but not aromatic), hydrocarbon radical of threeto ten carbon ring atoms. Fused bicyclic hydrocarbon radical includesbridged rings. Cycloalkyl includes spirocycloalkyl rings. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. One or two ringcarbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group.

In some embodiments, cycloalkyl includes but is not limited to:

“Cycloalkylene” means a divalent cycloalkyl group, as defined herein.

“Cycloalkylalkyl” means an alkyl group, as defined herein, substitutedwith at least one, in another example 1 or 2, cycloalkyl groups asdefined herein.

“Cycloalkylalkyloxy” means an —OR group where R is a cycloalkylalkylgroup as defined herein.

“Cycloalkyloxy” means an —OR group where R is cycloalkyl, as definedherein.

“Cycloalkylthio” means an —SR group where R is cycloalkyl, as definedherein.

“Dialkylamino” means an —NRR′ radical where R and R′ are independentlyalkyl as defined herein, or an N-oxide derivative, or a protectedderivative thereof. In some embodiments, dialkylamino includesdimethylamino, diethylamino, N,N-methylpropylamino orN,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with at least one,for example one or two, dialkylamino group(s), as defined herein.

“Dialkylaminocarbonyl” means a —C(O)NRR′ group where R and R′ are alkyl,as defined herein.

“Haloalkoxy” means an alkoxy group, as defined herein, substituted withone or more halo atoms, in another example by 1, 2, or 3 halo atoms.

“Haloalkyl” means an alkyl group substituted with one or more haloatoms, in another example by 1, 2, 3, 4, 5, or 6 halo atoms, in anotherexample by 1, 2, or 3 halo atoms. In some embodiments, haloalkylincludes, but is not limited to, trifluoromethyl, chloromethyl, and thelike.

“Heteroaryl” means monocyclic, fused bicyclic, or fused tricyclic,radical of 5 to 14 ring atoms containing one or more, in another exampleone, two, three, or four ring heteroatoms independently selected from—O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(H)—, and N-oxide, and theremaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic (but doesnot have to be a ring which contains a heteroatom, e.g.2,3-dihydrobenzo[b][1,4]dioxin-6-yl). One or two ring carbon atoms ofany nonaromatic rings comprising a bicyclic or tricyclic radical may bereplaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclic radicalincludes bridged ring systems. Unless stated otherwise, the valency maybe located on any atom of any ring of the heteroaryl group, valencyrules permitting.

In some embodiments, heteroaryl includes, but is not limited to,triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl,pyrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, indolyl,2,3-dihydro-1H-indolyl (including, for example,2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like),indazolyl, phthalimidyl, benzimidazolyl, benzoxazolyl, benzofuranyl,benzothienyl, benzopyranyl, benzothiazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridinyl, thiazolyl,benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,furo[2,3-d]thiazolyl, thieno[2,3-d]oxazolyl, thieno[3,2-b]furanyl,furo[2,3-d]pyrimidinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl, and7,8-dihydro-6H-cyclopenta[g]quinoxalinyl; and derivatives, N-oxide andprotected derivatives thereof.

“Heteroarylalkyl” means an alkyl group, as defined herein, substitutedwith one or two heteroaryl groups, as defined herein.

“Heteroaryloxy” means an —OR group where R is heteroaryl as definedherein.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 9 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedbicyclic group of 5 to 12 ring atoms in which one or more heteroatoms,for example one, two, three, or four ring heteroatoms, independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N═, —NH—, and N-oxide,the remaining ring atoms being carbon. One or two ring carbon atoms maybe replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclicradical includes bridged ring systems. Unless otherwise stated, thevalency of the group may be located on any atom of any ring within theradical, valency rules permitting. Heterocycloalkyl includesspiroheterocycloalkyl rings.

In some embodiments, heterocycloalkyl includes, but is not limited to,azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolinyl,2,5-dioxo-1H-pyrrolyl, 2,5-dioxo-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl,piperidinyl, 2-oxopiperidinyl, 4-piperidonyl, morpholinyl, piperazinyl,2-oxopiperazinyl, dioxopiperazinyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl,1,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl,dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, 2-azaspiro[3.3]heptanyl,7-azabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, and thederivatives thereof and N-oxide (for example 1-oxido-pyrrolidin-1-yl) ora protected derivative thereof.

“Heterocycloalkylalkyl” means an alkyl group substituted with at leastone, in another example 1 or 2, heterocycloalkyl groups, as definedherein.

“Heterocycloalkylalkyloxy” means an —OR group where R is anheterocycloalkylalkyl group, as defined herein.

“Heterocycloalkyloxy” means an —OR group where R is heterocycloalkyl, asdefined herein.

“Hydroxyalkyl” means an alkyl group, as defined herein, substituted with1, 2, or 3 hydroxy groups.

“Hydroxyalkyloxy” means an —OR group where R is hydroxyalkyl, as definedherein.

“Phenylalkyl” means an alkyl group, as defined herein, substituted withone or two phenyl groups.

“Phenyloxy” means an —OR group where R is phenyl.

The term “protecting group” refers to a removable group which modifiesthe reactivity of a functional group, for example, a hydroxyl, ketone oramine, against undesirable reaction during synthetic procedures and tobe later removed. Examples of hydroxy-protecting groups include, but notlimited to, methylthiomethyl, tert-dimethylsilyl,tert-butyldiphenylsilyl, ethers such as methoxymethyl, and estersincluding acetyl, benzoyl, and the like. Examples of ketone protectinggroups include, but not limited to, ketals, oximes, O-substituted oximesfor example O-benzyl oxime, O-phenylthiomethyl oxime,1-isopropoxycyclohexyl oxime, and the like. Examples of amine protectinggroups include, but are not limited to, tert-butoxycarbonyl (Boc) andcarbobenzyloxy (Cbz).

“Stereoisomers” include (but are not limited to) geometric isomers,enantiomers, diastereomers, and mixtures of geometric isomers,enantiomers or diastereomers. In some embodiments, individualstereoisomers of compounds are prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography and liberationof the optically pure product from the auxiliary or (2) directseparation of the mixture of optical enantiomers on chiralchromatographic column.

As used herein, “amelioration” of the symptoms of a particular disorderby administration of a particular compound or pharmaceutical compositionrefers to any lessening of severity, delay in onset, slowing ofprogression, or shortening of duration, whether permanent or temporary,lasting or transient that can be attributed to or associated withadministration of the compound or composition.

The term “carrier” includes pharmaceutically inert, inorganic or organiccarriers for the production of pharmaceutical compositions. Lactose,corn starch, or derivatives thereof, talc, stearic acid or its salts andthe like can be used, for example, as such carriers for tablets, coatedtablets, dragees and hard gelatin capsules. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active ingredient no carriers are, however, usually required in thecase of soft gelatin capsules, other than the soft gelatin itself.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, glycerol, vegetable oils and the like. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents include chemicalsused to stabilize compounds because they provide a more stableenvironment. Salts dissolved in buffered solutions (which also canprovide pH control or maintenance) are utilized as diluents in some orany embodiments, including, but not limited to a phosphate bufferedsaline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is determinedusing any suitable technique, such as a dose escalation study.

“Excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

“Pharmaceutically acceptable salt” refers to a formulation of a compoundthat does not cause significant irritation to an organism to which it isadministered and does not abrogate the biological activity andproperties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt s notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compound of the present invention forms with a baseinclude the following: salts thereof with inorganic bases such assodium, potassium, magnesium, calcium, and aluminum; salts thereof withorganic bases such as methylamine, ethylamine and ethanolamine; saltsthereof with basic amino acids such as lysine and ornithine; andammonium salt. The salts may be acid addition salts, which arespecifically exemplified by acid addition salts with the following:mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, nitric acid, and phosphoric acid:organic acids suchas formic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonicacid; acidic amino acids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to:intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary andtopical administration.

“Subject” refers to an animal, including, but not limited to, a primate(e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

“Treat,” “treating,” and “treatment,” in the context of treating adisease or disorder, are meant to include alleviating or abrogating adisorder, disease, or condition, or one or more of the symptomsassociated with the disorder, disease, or condition; or to slowing theprogression, spread or worsening of a disease, disorder or condition orof one or more symptoms thereof. Often, the beneficial effects that asubject derives from a therapeutic agent do not result in a completecure of the disease, disorder or condition.

EMBODIMENTS

The following paragraphs present a number of embodiments of thecompounds disclosed herein. In each instance the embodiment includesboth the recited compound(s) as well as a single stereoisomer or mixtureof stereoisomers thereof, as well as a pharmaceutically acceptable saltthereof. The compounds include the N-oxides or pharmaceuticallyacceptable salts thereof. In some situations, the compounds exist astautomers. All tautomers are included within the scope of the compoundspresented herein.

The compounds described herein, as well as their correspondingpharmaceutically acceptable salts thereof, can exist inisotopically-labeled form, in which one or more atoms of the compoundsare replaced by an atom having the same atomic number but an atomic massdifferent from the atomic mass usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, and chloride, such as ²H (deuterium), ³H (tritium),¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Isotopically labeled compounds of the present invention, as well aspharmaceutically acceptable salts thereof, generally can be prepared bycarrying out the procedures disclosed in the Schemes and/or in theExamples and Preparations herein, by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

In the compounds of the invention, unless otherwise stated, any atom notspecifically designated as a particular isotope is meant to representany stable isotope of that atom at is natural abundance. When a positionis designated as “H” or “hydrogen,” the position is to be understood tohave hydrogen at is naturally abundant isotopic composition, with theunderstanding that some variation of natural isotopic abundance occursin a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. When a particular position isdesignated as “D” or “deuterium,” it is to be understood that theabundance of deuterium at that position is substantially greater thanthe natural abundance of deuterium, with is 0.015%, and typically has atleast 50% deuterium incorporation at that position.

The methods disclosed herein also include methods of treating diseasesby administering deuterated compounds of the invention or otherisotopically-labeled compounds of the invention alone or aspharmaceutical compositions. In some of these situations, substitutionof hydrogen atoms with heavier isotopes such as deuterium can affordcertain therapeutic advantages resulting from greater metabolicstability (for example, increased in vivo half-life or reduced dosagerequirements). Moreover, certain isotopically-labeled compounds, forexample those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays such as positron emission tomography (PET). Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are useful for these embodiments.

In one aspect, provided is a compound of Formula I:

where

-   R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);-   X¹ is alkylene, alkenylene, or cycloalkylene;-   R^(1a) is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl    each of which is optionally substituted with 1, 2, or 3 R⁷ groups;-   R² is hydrogen, hydroxy, or alkyl; and R³ is alkyl, aminoalkyl,    alkylaminoalkyl, or dialkylaminoalkyl; R² and R³ together with the    nitrogen to which they are attached form a 3-10 membered    heterocycloalkyl ring, optionally substituted with 1, 2, 3, 4, 5, 6,    7, or 8 R⁸;-   R⁴ is aryl or heteroaryl each of which is optionally substituted    with 1, 2, 3, or 4 R⁹ groups;-   R⁵ is halo, —OH, —OTBS, —N₃, —NH₂, —NH(OCH₃), —NHC(O)CH₃, or    —NHC(O)H; and R^(5a) is hydrogen, alkyl, or deuterium; or R⁵ and    R^(5a) together with the carbon to which they are attached form C(O)    or —C(NOH);-   R⁶ is halo or deuterium; and R^(6a) is hydrogen, halo, or deuterium;    or R⁶ and R^(6a) together with the carbon to which they are attached    form C(═NOR¹⁰) or —C(O);-   each R⁷, when present, is independently nitro, cyano, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl,    heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl,    heteroarylalkyl, or heteroaryloxy; where the phenyl and the    heteroaryl, either alone or as part of another group, are    independently optionally substituted with 1, 2 or 3 R^(7a);-   each R^(7a), when present, is independently selected from cyano,    halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;-   each R⁸, when present, is independently deuterium, amino,    alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl,    or cycloalkyl; or two R⁸ together with the carbon to which they are    attached form C(O);-   each R⁹, when present, is independently cyano, nitro, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl,    —NR¹¹C(O)NR^(11a)R^(11b), hydroxy, alkoxy, alkenyloxy,    hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy,    cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy,    heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and    the phenyl, either alone or as part of another group, are    independently optionally substituted with 1 or 2 R^(9a);-   each R^(9a), when present, is independently selected from alkyl,    hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino,    alkylamino, and dialkylamino;-   R¹⁰ is hydrogen, alkyl, or phenyl;-   R¹¹, R^(11a), and R^(11b) are independently hydrogen, alkyl, or    cycloalkyl; and-   R¹² is hydrogen or C₁₋₅ alkyl; optionally a tautomer, a single    stereoisomer or mixture of stereoisomers thereof and additionally    optionally a pharmaceutically acceptable salt thereof.

In some or any embodiments, the compound of Formula I is that where

-   R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);-   X¹ is alkylene, alkenylene, or cycloalkylene;-   R^(1a) is alkyl, heterocycloalkyl, aryl or heteroaryl each of which    is optionally substituted with 1, 2, or 3 R⁷ groups;-   R² and R³ together with the nitrogen to which they are attached form    a 3-10 membered heterocycloalkyl ring, optionally substituted with    1, 2, 3, 4, 5, 6, 7, or 8 R⁸;-   R⁴ is aryl or heteroaryl each of which is optionally substituted    with 1, 2, 3, or 4 R⁹ groups;-   R⁵ is —OH, and R^(5a) is hydrogen;-   R⁶ and R^(6a) are halo; R⁶ and R^(6a) are deuterium; or R⁶ and    R^(6a) together with the carbon to which they are attached form    C(═NOH) or C(O);-   each R⁷, when present, is independently nitro, cyano, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl,    heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl,    heteroarylalkyl, or heteroaryloxy; where the phenyl and the    heteroaryl, either alone or as part of another group, are    independently optionally substituted with 1, 2 or 3 R^(7a);-   each R^(7a), when present, is independently selected from cyano,    halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;-   each R⁸, when present, is independently deuterium, amino,    alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl,    or cycloalkyl; or two R⁸ together with the carbon to which they are    attached form C(O);-   each R⁹, when present, is independently cyano, nitro, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy,    alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio,    cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl,    heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the    heterocycloalkyl and the phenyl, either alone or as part of another    group, are independently optionally substituted with 1 or 2 R^(9a);-   each R^(9a), when present, is independently selected from alkyl,    hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino,    alkylamino, and dialkylamino; and-   R¹² is hydrogen or C₁₋₅ alkyl; optionally a tautomer, a single    stereoisomer or mixture of stereoisomers thereof and additionally    optionally a pharmaceutically acceptable salt thereof.

In some or any embodiments, the compound of Formula I is that where

-   R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);-   X¹ is alkylene, alkenylene, or cycloalkylene;-   R^(1a) is alkyl, heterocycloalkyl, aryl or heteroaryl each of which    is optionally substituted with 1, 2, or 3 R⁷ groups;-   R² and R³ together with the nitrogen to which they are attached form    a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered    bicyclic heterocycloalkyl; each of which is optionally substituted    with 1 or 2 R⁸;-   R⁴ is aryl or heteroaryl each of which is optionally substituted    with 1, 2, or 3 R⁹ groups;-   R⁵ is —OH, and R^(5a) is hydrogen;-   R⁶ and R^(6a) are halo; or R⁶ and R^(6a) together with the carbon to    which they are attached form C(═NOH) or C(O);-   each R⁷, when present, is independently nitro, cyano, halo,    haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or    heteroaryloxy; where the phenyl and the heteroaryl, either alone or    as part of another group, are independently optionally substituted    with 1, 2 or 3 R^(7a);-   each R^(7a), when present, is independently selected from cyano,    halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;-   each R⁸, when present, is independently amino, alkylamino,    dialkylamino, alkyl, halo, or cycloalkyl; or two R⁸ together with    the carbon to which they are attached form C(O);-   each R⁹, when present, is independently cyano, nitro, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy,    alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio,    cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl,    heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the    heterocycloalkyl and the phenyl, either alone or as part of another    group, are independently optionally substituted with 1 or 2 R^(9a);-   each R^(9a), when present, is independently selected from alkyl,    hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino,    alkylamino, and dialkylamino; and-   R¹² is hydrogen or CH₃;    optionally a tautomer, a single stereoisomer or mixture of    stereoisomers thereof and additionally optionally a pharmaceutically    acceptable salt thereof.

In some or any embodiments, the compound of Formula I is that where

-   R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);-   X¹ is alkylene or alkenylene;-   R^(1a) is heterocycloalkyl, aryl or heteroaryl each of which is    optionally substituted with 1 or 2 R⁷ groups;-   R² and R³ together with the nitrogen to which they are attached form    a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered    bicyclic heterocycloalkyl; each of which is optionally substituted    with 1 or 2 R⁸;-   R⁴ is aryl or heteroaryl each of which is optionally substituted    with 1, 2, or 3 R⁹ groups;-   R⁵ is —OH, and R^(5a) is hydrogen;-   R⁶ and R^(6a) are halo; or R⁶ and R^(6a) together with the carbon to    which they are attached form C(═NOH) or C(O);-   each R⁷, when present, is independently cyano, halo, haloalkyl,    alkyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl,    phenyloxy, heteroaryl, or heteroaryloxy; where the phenyl and the    heteroaryl, either alone or as part of another group, are    independently optionally substituted with 1 or 2 R^(7a);-   each R^(7a), when present, is independently selected from cyano,    halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;-   each R⁸, when present, is independently amino, alkyl, or halo; or    two R⁸ together with the carbon to which they are attached form    C(O);-   each R⁹, when present, is independently amino, halo, haloalkyl,    alkyl, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy,    cycloalkylthio, cycloalkyloxy, heterocycloalkyloxy,    heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and    the phenyl, either alone or as part of another group, are    independently optionally substituted with 1 or 2 R^(9a);-   each R^(9a), when present, is independently selected from alkyl or    halo;-   R¹⁰ is hydrogen or CH₃;-   R¹² is hydrogen; and-   optionally a tautomer, a single stereoisomer or mixture of    stereoisomers thereof and additionally optionally a pharmaceutically    acceptable salt thereof.

In some or any embodiments, the compound of Formula I is that where

-   R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);-   X¹ is alkylene;-   R^(1a) is heterocycloalkyl, aryl or heteroaryl each of which is    optionally substituted with 1, 2, or 3 R⁷ groups;-   R² and R³ together with the nitrogen to which they are attached form    a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered    bicyclic heterocycloalkyl; each of which is optionally substituted    with 1 or 2 R⁸;-   R⁴ is aryl or heteroaryl each of which is optionally substituted    with 1, 2, or 3 R⁹ groups;-   R⁵ is —OH, and R^(5a) is hydrogen;-   R⁶ and R^(6a) are halo; or R⁶ and R^(6a) together with the carbon to    which they are attached form or C(O);-   each R⁷, when present, is independently nitro, cyano, halo,    haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or    heteroaryloxy; where the phenyl and the heteroaryl, either alone or    as part of another group, are independently optionally substituted    with 1, 2 or 3 R^(7a);-   each R^(7a), when present, is independently selected from cyano,    halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;-   each R⁸, when present, is independently amino, alkylamino,    dialkylamino, alkyl, or halo;-   each R⁹, when present, is independently amino, alkylamino,    dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy,    hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy,    cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy,    heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and    the phenyl, either alone or as part of another group, are    independently optionally substituted with 1 or 2 R^(9a);-   each R^(9a), when present, is independently selected from alkyl and    halo; and-   R¹² is hydrogen or CH₃;    optionally a tautomer, a single stereoisomer or mixture of    stereoisomers thereof and additionally optionally a pharmaceutically    acceptable salt thereof.

In another aspect, provided is a compound of Formula II:

where

-   R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);-   X¹ is alkylene, alkenylene, or cycloalkylene;-   R^(1a) is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl    each of which is optionally substituted with 1, 2, or 3 R⁷ groups;-   R² is hydrogen, hydroxy, or alkyl; and R³ is alkyl, aminoalkyl,    alkylaminoalkyl, or dialkylaminoalkyl; or R² and R³ together with    the nitrogen to which they are attached form a 3-10 membered    heterocycloalkyl ring which is optionally substituted with 1, 2, 3,    or 4 R⁸;-   R⁴ is aryl or heteroaryl each of which is optionally substituted    with 1, 2, or 3 R⁹ groups;-   R⁵ is halo, —OH, —OTBS, —N₃, —NH₂, —NH(OCH₃), —NHC(O)CH₃, or    —NHC(O)H and R^(5a) is hydrogen, alkyl, or deuterium; or R⁵ and    R^(5a) together with the carbon to which they are attached form C(O)    or C(NOH);-   R⁶ is halo or deuterium; and R^(6a) is hydrogen, halo, or deuterium;    or R⁶ and R^(6a) together with the carbon to which they are attached    form C(NOR¹⁰) or —C(O);-   each R⁷, when present, is independently nitro, cyano, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy,    haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl, dialkylaminocarbonyl, or heteroaryl;-   each R⁸, when present, is independently deuterium, amino,    alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl,    or cycloalkyl;-   each R⁹, when present, is independently cyano, nitro, amino,    alkylamino, dialkylamino, halo, haloalkyl, alkyl,    —NR¹¹C(O)NR^(11a)R^(11b), hydroxy, alkoxy, haloalkoxy,    cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyloxy, or    heterocycloalkylalkyloxy which is optionally substituted with 1 or 2    hydroxy;-   R¹⁰ is hydrogen, alkyl, or phenyl;-   R¹¹, R^(11a), and R^(11b) are independently hydrogen, alkyl, or    cycloalkyl; and    optionally a tautomer, a single stereoisomer or mixture of    stereoisomers thereof and additionally optionally a pharmaceutically    acceptable salt thereof.

In some or any embodiments, the compound of Formula I or II is thatwhere R¹ is —C(O)C(R⁶)(R^(6a))R^(1a); and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R¹ is —C(O)C(R⁶)(R^(6a))R^(1a); R⁶ and R^(6a) arehalo; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R¹ is—C(O)CF₂R^(1a); and all other groups are as defined in the Summary ofthe Invention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R¹ is—C(O)C(R⁶)(R^(6a))R^(1a); R⁶ is halo and R^(6a) is hydrogen; and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R¹ is —C(O)C(H)(F)R^(1a); andall other groups are as defined in the Summary of the Invention or anyof the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R¹ is —C(O)CD₂R^(1a); and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R¹ is—C(O)C(R⁶)(R^(6a))R^(1a); R⁶ and R^(6a) together with the carbon towhich they are attached form C(═NOR¹⁰); and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R¹ is —C(O)C(R⁶)(R^(6a))R^(1a); R⁶ and R^(6a)together with the carbon to which they are attached form C(O); and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R¹ is —C(O)C(R⁶)(R^(6a))—X¹—R^(1a); and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R¹ is —C(O)C(R⁶)(R^(6a))—X¹—R^(1a); R⁶ and R^(6a)are halo; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R¹ is—C(O)CF₂—X¹—R^(1a); and all other groups are as defined in the Summaryof the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R¹ is —C(O)C(R⁶)(R^(6a))—X¹—R^(1a); X¹ is alkylene; and all othergroups are as defined in the Summary of the Invention or any of theembodiments described herein. In some or any embodiments, the compoundof Formula I or II is that where R¹ is —C(O)C(R⁶)(R^(6a))—CH₂—R^(1a);and all other groups are as defined in the Summary of the Invention orany of the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R¹ is—C(O)C(R⁶)(R^(6a))—CH₂CH₂CH₂—R^(1a); and all other groups are as definedin the Summary of the Invention or any of the embodiments describedherein. In some or any embodiments, the compound of Formula I or II isthat where R¹ is —C(O)C(R⁶)(R^(6a))—X¹—R^(1a); X¹ is alkenylene; and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R¹ is—C(O)C(R⁶)(R^(6a))—X—R^(1a); X² is —CH═CH— or —C(CH₂)CH₂—; and all othergroups are as defined in the Summary of the Invention or any of theembodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R¹ is —C(O)C(R⁶)(R^(6a))—X¹—R^(1a) which is—C(O)C(halo)₂CH₂R^(1a), —C(O)C(halo)₂CH₂CH₂R^(1a),—C(O)C(O)CH₂CH₂R^(1a), —C(O)C(═NOH)CH₂CH₂R^(1a),—C(O)C(═NOCH₃)CH₂CH₂R^(1a), —C(O)C(halo)₂-CH═CHR^(1a), or—C(O)C(halo)₂-C(═CH₂)CH₂R^(1a); and all other groups are as defined inthe Summary of the Invention or any of the embodiments described herein.In some or any embodiments, the compound of Formula I or II is thatwhere R¹ is —C(O)C(R⁶)(R^(6a))—X¹—R^(1a) which is —C(O)CF₂CH₂R^(1a),—C(O)CF₂CH₂CH₂R^(1a), —C(O)CF₂—CH═CHR^(1a), or—C(O)CF₂—C(═CH₂)CH₂R^(1a); and all other groups are as defined in theSummary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R¹ is —C(O)C(R⁶)(R^(6a))R^(1a); R⁶ and R^(6a) together with thecarbon to which they are attached form C(O); and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R^(1a) is alkyl optionally substituted with 1, 2, or 3 R⁷ groups;and all other groups are as defined in the Summary of the Invention orany of the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R^(1a) is methyl; and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R^(1a) is aryl optionally substituted with 1, 2, or 3 R⁷ groups;and all other groups are as defined in the Summary of the Invention orany of the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R^(1a) is naphthyl optionallysubstituted with 1 or 2 R⁷ groups; and all other groups are as definedin the Summary of the Invention or any of the embodiments describedherein. In some or any embodiments, the compound of Formula I or II isthat where R^(1a) is naphthyl optionally substituted with 1 or 2 R⁷groups and each R⁷, when present, is halo; and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R^(1a) is indanyl optionally substituted with 1 or 2R⁷ groups; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R^(1a) isindanyl optionally substituted with 1 or 2 R⁷ groups and each R⁷, whenpresent, is independently heteroaryl (in another example pyridinyl) orhalo; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R^(1a) isphenyl optionally substituted with 1, 2, or 3 R⁷ groups; and all othergroups are as defined in the Summary of the Invention or any of theembodiments described herein. In some or any embodiments, the compoundof Formula I or II is that where R^(1a) is phenyl optionally substitutedwith 1 or 2 R⁷ groups and each R⁷, when present, is independently halo,haloalkoxy, or heteroaryl (in another example pyridinyl); and all othergroups are as defined in the Summary of the Invention or any of theembodiments described herein. In some or any embodiments, the compoundof Formula I or II is that where R^(1a) is phenyl optionally substitutedwith 1 or 2 R⁷ groups and each R⁷, when present, is independently arylor heteroaryl; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R^(1a) isphenyl optionally substituted with 1 or 2 R⁷ groups and each R⁷, whenpresent, is independently phenyl or heteroaryl; and all other groups areas defined in the Summary of the Invention or any of the embodimentsdescribed herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R^(1a) is heteroaryl optionally substituted with 1, 2, or 3 R⁷groups; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R^(1a) isfused bicyclic heteroaryl optionally substituted with 1, 2, or 3 R⁷groups; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R^(1a) isbenzofuranyl, benzothienyl, indolyl, benzimidazolyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl, benzothiazolyl,furo[3,2-c]pyridinyl, pyrrolo[1,2-b]pyridazinyl,imidazo[1,2-a]pyridinyl, furo[3,2-b]pyridinyl, furo[2,3-d]pyrimidinyl,thieno[3,2-b]furanyl, thieno[2,3-d]oxazolyl, or furo[2,3-d]thiazolyl,each of which is optionally substituted with 1 or 2 R⁷ groups; and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R^(1a) is benzofuranyl,benzothienyl, indolyl, benzimidazolyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl, or benzothiazolyl, each of whichis optionally substituted with 1 or 2 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R^(1a) is benzofuranyl optionally substituted with 1or 2 R⁷ groups; and all other groups are as defined in the Summary ofthe Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R^(1a) is fused bicyclic heteroaryl optionally substituted with 1,2, or 3 R⁷ groups where each R⁷, when present, is independently halo,alkyl, or haloalkyl; and all other groups are as defined in the Summaryof the Invention or any of the embodiments described herein. In some orany embodiments, the compound of Formula I or II is that where R^(1a) isfused bicyclic heteroaryl optionally substituted with 1, 2, or 3 R⁷groups where each R⁷, when present, is independently chloro, bromo,fluoro, methyl, or trifluoromethyl; and all other groups are as definedin the Summary of the Invention or any of the embodiments describedherein.

In some or any embodiments, the compound of Formula I or II is thatwhere R^(1a) is fused tricyclic heteroaryl optionally substituted with1, 2, or 3 R⁷ groups; and all other groups are as defined in the Summaryof the Invention or any of the embodiments described herein. In some orany embodiments, the compound of Formula I or II is that where R^(1a) is7,8-dihydro-6H-cyclopenta[g]quinoxalinyl; and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein.

In some or any embodiments, the compound of Formula I or II is thatwhere each R⁷, when present, is independently optionally substitutedwith 1, 2 or 3 R^(7a) groups, where each R^(7a), when present, isindependently cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, andcycloalkyl; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where each R⁷, whenpresent, is aryl or heteroaryl, either alone or as part of anothergroup, such aryl or heteroaryl is independently optionally substitutedwith 1, 2 or 3 R^(7a) groups, as described herein. In some or anyembodiments, the compound of Formula I or II is that where each R⁷, whenpresent, is phenyl or heteroaryl, either alone or as part of anothergroup, such phenyl or heteroaryl is independently optionally substitutedwith 1, 2 or 3 R^(7a) groups, as described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R² is hydrogen, hydroxy, or alkyl; and R³ is alkyl, aminoalkyl,alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R² is hydroxy and R³ is alkyl; and all other groupsare as defined in the Summary of the Invention or any of the embodimentsdescribed herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R² and R³ together with the nitrogen to which they are attachedform a 3-10 membered heterocycloalkyl ring which is optionallysubstituted with 1, 2, 3, or 4 R⁸; and all other groups are as definedin the Summary of the Invention or any of the embodiments describedherein. In some or any embodiments, the compound of Formula I or II isthat where R² and R³ together with the nitrogen to which they areattached form a 4-8 membered heterocycloalkyl ring which is optionallysubstituted with 1, 2, 3, or 4 R⁸; and all other groups are as definedin the Summary of the Invention or any of the embodiments describedherein. In some or any embodiments, the compound of Formula I or II isthat where R² and R³ together with the nitrogen to which they areattached form azetidinyl, pyrrolidinyl, 2-azabicyclo[2.2.1]heptanyl,7-azabicyclo[2.2.1]heptanyl, 2-azaspiro[3.3]heptanyl,1-oxidopyrrolidinyl, piperidinyl, piperazinyl, or8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with1 or 2 R⁸; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R² and R³together with the nitrogen to which they are attached form pyrrolidinyloptionally substituted with 1, 2, 3, or 4 R⁸; and all other groups areas defined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R² and R³ together with the nitrogen to which theyare attached form pyrrolidinyl optionally substituted with 1 or 2 R⁸;and all other groups are as defined in the Summary of the Invention orany of the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R² and R³ together with thenitrogen to which they are attached form pyrrolidinyl optionallysubstituted with 1, 2, 3, or 4 R⁸ where each R⁸, when present, isindependently deuterium, amino, alkyl, halo, or cycloalkyl; and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R² and R³ together with thenitrogen to which they are attached form unsubstituted pyrrolidinyl; andall other groups are as defined in the Summary of the Invention or anyof the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R² and R³ together with thenitrogen to which they are attached form azetidinyl optionallysubstituted with 1 or 2 R⁸; and all other groups are as defined in theSummary of the Invention or any of the embodiments described herein. Insome or any embodiments, the compound of Formula I or II is that whereR² and R³ together with the nitrogen to which they are attached formazetidinyl optionally substituted with 1 or 2 R⁸ where each R⁸, whenpresent, is independently alkyl; and all other groups are as defined inthe Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R² and R³ together with the nitrogen to which they are attachedform a 3-10 membered heterocycloalkyl ring which is optionallysubstituted with 1, 2, 3, or 4 R⁸ where each R⁸, when present, isindependently deuterium, amino, alkyl, halo, or cycloalkyl; and allother groups are as defined in the Summary of the Invention or any ofthe embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R² and R³ together with thenitrogen to which they are attached form a 3-10 memberedheterocycloalkyl ring which is optionally substituted with 1, 2, 3, or 4R⁸ where each R⁸, when present, is independently deuterium, amino,methyl, fluoro, or cyclopropyl; and all other groups are as defined inthe Summary of the Invention or any of the embodiments described herein.In some or any embodiments, the compound of Formula I or II is thatwhere R² and R³ together with the nitrogen to which they are attachedform a 3-10 membered heterocycloalkyl ring which is optionallysubstituted with 1 or 2 R⁸ where each R⁸, when present, is independentlyamino, methyl, fluoro, or cyclopropyl; and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups; andall other groups are as defined in the Summary of the Invention or anyof the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R⁴ is phenyl optionallysubstituted with 1, 2, or 3 R⁹ groups; and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R⁴ is phenyl optionally substituted with 1, 2, or 3R⁹ groups where each R⁹, when present, is independently halo, alkoxy,haloalkyl, haloalkoxy, cycloalkyloxy, heterocycloalkyloxy, orheterocycloalkylalkyloxy which is optionally substituted with onehydroxy; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R⁴ is phenyloptionally substituted with 1 or 2 R⁹ groups where each R⁹, whenpresent, is independently bromo, chloro, fluoro, methoxy,difluoromethyl, trifluoromethyl, trifluoromethoxy, cyclopropyloxy,tetrahydrofuranyloxy, or tetrahydropyranylmethyl which is optionallysubstituted with one hydroxy; and all other groups are as defined in theSummary of the Invention or any of the embodiments described herein. Insome or any embodiments, the compound of Formula I or II is that whereR⁴ is phenyl optionally substituted with 2 R⁹ groups one of which ishalo, and one of which is alkoxy; and all other groups are as defined inthe Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R⁴ is heteroaryl optionally substituted with 1, 2, or 3 R⁹ groups;and all other groups are as defined in the Summary of the Invention orany of the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R⁴ is pyridinyl, 1H-indazolyl,benzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, or quinolinyl each ofwhich is optionally substituted with 1 or 2 R⁹ groups; and all othergroups are as defined in the Summary of the Invention or any of theembodiments described herein. In some or any embodiments, the compoundof Formula I or II is that where R⁴ is pyridinyl, 1H-indazolyl,benzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, or quinolinyl; R⁹,when present, is halo, alkyl, alkoxy, haloalkoxy, cycloalkyloxy, orheterocycloalkylalkyloxy which is optionally substituted with onehydroxy; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R⁴ ispyridinyl, 1H-indazolyl, benzofuranyl,2,3-dihydrobenzo[b][1,4]dioxin-6-yl, or quinolinyl; R⁹, when present, ischloro, fluoro, methyl, methoxy, isopropoxy, 2,2,2-trifluoroethoxy,cyclopropyloxy, or tetrahydropyranylmethyl which is optionallysubstituted with one hydroxy; and all other groups are as defined in theSummary of the Invention or any of the embodiments described herein. Insome or any embodiments, the compound of Formula I or II is that whereR⁴ is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxin-6-yl; and all othergroups are as defined in the Summary of the Invention or any of theembodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R⁵ is R⁵ is halo, —OH, —OTBS, —N₃, —NH₂, —NH(OCH₃), —NHC(O)CH₃, or—NHC(O)H and R^(5a) is hydrogen, alkyl, or deuterium; or R⁵ and R^(5a)together with the carbon to which they are attached form C(O) or C(NOH);and all other groups are as defined in the Summary of the Invention orany of the embodiments described herein. In some or any embodiments, thecompound of Formula I or II is that where R⁵ is —OH, —NH₂, —NH(OCH₃),—NHC(O)CH₃, or —NHC(O)H and R^(5a) is hydrogen, alkyl, or deuterium; orR⁵ and R^(5a) together with the carbon to which they are attached formC(O) or —C(NOH); and all other groups are as defined in the Summary ofthe Invention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R⁵ is OH andR^(5a) is hydrogen; and all other groups are as defined in the Summaryof the Invention or any of the embodiments described herein. In some orany embodiments, the compound of Formula I or II is that where R⁵ is—NH₂ and R^(5a) is hydrogen; and all other groups are as defined in theSummary of the Invention or any of the embodiments described herein. Insome or any embodiments, the compound of Formula I or II is that whereR⁵ is OH and R^(5a) is deuterium; and all other groups are as defined inthe Summary of the Invention or any of the embodiments described herein.In some or any embodiments, the compound of Formula I or II is thatwhere R⁵ is —NH(OCH₃) and R^(5a) is hydrogen; and all other groups areas defined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R⁵ is OH and R^(5a) is alkyl; and all other groupsare as defined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R⁵ is —NHC(O)H and R^(5a) is hydrogen; and all othergroups are as defined in the Summary of the Invention or any of theembodiments described herein. In some or any embodiments, the compoundof Formula I or II is that where R⁵ and R^(5a) together with the carbonto which they are attached form C(O); and all other groups are asdefined in the Summary of the Invention or any of the embodimentsdescribed herein. In some or any embodiments, the compound of Formula Ior II is that where R⁵ and R^(5a) together with the carbon to which theyare attached form C(NOH); and all other groups are as defined in theSummary of the Invention or any of the embodiments described herein. Insome or any embodiments, the compound of Formula I or II is that whereR⁵ is OH and R^(5a) is hydrogen, R⁵ is —NH₂ and R^(5a) is hydrogen, R⁵is OH and R^(5a) is deuterium, R⁵ is —NH(OCH₃) and R^(5a) is hydrogen,R⁵ is OH and R^(5a) is alkyl, R⁵ is —NHC(O)H and R^(5a) is hydrogen, R⁵and R^(5a) together with the carbon to which they are attached formC(O), or R⁵ and R^(5a) together with the carbon to which they areattached form C(NOH); and all other groups are as defined in the Summaryof the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is thatwhere R¹⁰ is hydrogen; and all other groups are as defined in theSummary of the Invention or any of the embodiments described herein. Insome or any embodiments, the compound of Formula I or II is that whereR¹⁰ is alkyl; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R¹⁰ ismethyl; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein. In some or anyembodiments, the compound of Formula I or II is that where R¹⁰ isphenyl; and all other groups are as defined in the Summary of theInvention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(a):

where all groups are as defined in the Summary of the Invention or asdefined in any of the above embodiments. In another embodiment, thecompound of Formula I(a) is that where R^(5a) is hydrogen; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(a) is that where R⁵ is OH; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(a) is that where R¹ is —C(O)C(R⁶)(R^(6a))R^(1a); and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(a) is that where R⁴ is heteroaryl optionallysubstituted with 1, 2, or 3 R⁹ groups; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(a) is that where R⁴ is aryl optionally substituted with 1, 2,or 3 R⁹ groups; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(a) is that where R² andR³ together with the nitrogen to which they are attached form a 3-10membered heterocycloalkyl ring which is optionally substituted with 1,2, or 3 R⁸; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(b) or I(c):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(b) or I(c) is that where R⁵ is OH;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(b) or I(c) is that where R¹ is—C(O)C(R⁶)(R^(6a))R^(1a); and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(b) orI(c) is that where R¹ is —C(O)C(R⁶)(R^(6a))R^(1a); R^(1a) isunsubstituted indanyl; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(b) orI(c) is that where R⁴ is heteroaryl optionally substituted with 1, 2, or3 R⁹ groups; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(b) or I(c) is that whereR⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(b) or I(c) is that where R² and R³together with the nitrogen to which they are attached form a 3-10membered heterocycloalkyl ring which is optionally substituted with 1,2, or 3 R⁸; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(d):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(d) is that where R⁵ is OH; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(d) is that where R⁴ is heteroaryloptionally substituted with 1, 2, or 3 R⁹ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(d) is that where R⁴ is aryl optionally substituted with 1, 2,or 3 R⁹ groups; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(d) is that where R² andR³ together with the nitrogen to which they are attached form a 3-10membered heterocycloalkyl ring which is optionally substituted with 1,2, or 3 R⁸; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(d) is that where R⁶ andR^(6a) are halo; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(d) is that where R^(1a)is heteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(d) is that where at least one R⁷is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(e):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(e) is that where R⁵ is OH; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(e) is that where R² and R³together with the nitrogen to which they are attached form a 3-10membered heterocycloalkyl ring which is optionally substituted with 1,2, or 3 R⁸; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(e) is that where R⁶ andR^(6a) are halo; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(e) is that where R^(1a)is heteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(e) is that where at least one R⁷is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(f):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(f) is that where R⁵ is OH; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(f) is that where R² and R³together with the nitrogen to which they are attached form a 3-10membered heterocycloalkyl ring which is optionally substituted with 1,2, or 3 R⁸; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(f) is that where R⁶ andR^(6a) are halo; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(f) is that where atleast one R⁷ is halo; and all other groups are as defined in the Summaryof the Invention or as defined in any of the embodiments describedherein. In another embodiment, the compound of Formula I(f) is thatwhere R⁴ is heteroaryl optionally substituted with 1, 2, or 3 R⁹ groups;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(f) is that where R⁴ is aryloptionally substituted with 1, 2, or 3 R⁹ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(g):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(g) is that where R⁵ is OH; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(g) is that where R⁴ is heteroaryloptionally substituted with 1, 2, or 3 R⁹ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(g) is that where R⁴ is unsubstituted2,3-dihydrobenzo[b][1,4]dioxinyl; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(g) isthat where R⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(g) is that where R^(1a) isheteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(g) is that where at least one R⁷is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(g) is that where R^(1a) isbenzofuranyl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(s):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(s) is that where R⁵ is OH; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(s) is that where R⁴ is heteroaryloptionally substituted with 1, 2, or 3 R⁹ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(s) is that where R⁴ is unsubstituted2,3-dihydrobenzo[b][1,4]dioxinyl; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(s) isthat where R⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(s) is that where R^(1a) isheteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(s) is that where at least one R⁷is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(s) is that where R^(1a) isbenzofuranyl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein.

In another embodiment, the compound of Formula I(s) is that where R^(1a)is benzothiophene optionally substituted with 1, 2, or 3 R⁷ groups; andall other groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(s) is that where R^(1a) is aryloptionally substituted with 1, 2, or 3 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(s) is that where R^(1a) is phenyl optionally substituted with1, 2, or 3 R⁷ groups; and all other groups are as defined in the Summaryof the Invention or as defined in any of the embodiments describedherein. In another embodiment, the compound of Formula I(s) is thatwhere at least one R⁷ is halo; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(s) isthat where R⁷ is phenyl or heteroaryl optionally substituted with atleast one R^(7a); and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(s) is that where atleast one R^(7a) is halo; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein.

In some or any embodiments, the compound of Formula I is according toFormula I(t):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(t) is that where R⁵ is OH; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(t) is that where R⁴ is heteroaryloptionally substituted with 1, 2, or 3 R⁹ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(t) is that where R⁴ is unsubstituted2,3-dihydrobenzo[b][1,4]dioxinyl; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(t) isthat where R⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(t) is that where R^(1a) isheteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(t) is that where at least one R⁷is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(t) is that where R^(1a) isbenzofuranyl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(u):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(u) is that where R⁵ is OH; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(u) is that where R⁴ is heteroaryloptionally substituted with 1, 2, or 3 R⁹ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(u) is that where R⁴ is unsubstituted2,3-dihydrobenzo[b][1,4]dioxinyl; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(u) isthat where R⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(u) is that where R^(1a) isheteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(u) is that where at least one R⁷is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(u) is that where R^(1a) isbenzofuranyl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(v), Formula I(v′), or Formula I(v″):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(v), Formula I(v′), or FormulaI(v″) is that where R² and R³ together with the nitrogen to which theyare attached form a 3-10 membered heterocycloalkyl ring which isoptionally substituted with 1, 2, or 3 R⁸; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(v), Formula I(v′), or Formula I(v″) is that where R⁵ is OH;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(v), Formula I(v′), or FormulaI(v″) is that where R⁴ is heteroaryl optionally substituted with 1, 2,or 3 R⁹ groups; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(v), Formula I(v′), orFormula I(v″) is that where R⁴ is unsubstituted2,3-dihydrobenzo[b][1,4]dioxinyl; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(v),Formula I(v′), or Formula I(v″) is that where R⁴ is aryl optionallysubstituted with 1, 2, or 3 R⁹ groups; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(v), Formula I(v′), or Formula I(v″) is that where at least oneR⁹ is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(v), Formula I(v′), orFormula I(v″) is that where at least one R⁹ is alkoxy; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(v), Formula I(v′), or Formula I(v″) is that whereR^(1a) is heteroaryl optionally substituted with 1, 2, or 3 R⁷ groups;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(v), Formula I(v′), or FormulaI(v″) is that where R^(1a) is benzofuranyl optionally substituted with1, 2, or 3 R⁷ groups; and all other groups are as defined in the Summaryof the Invention or as defined in any of the embodiments describedherein. In another embodiment, the compound of Formula I(v), FormulaI(v′), or Formula I(v″) is that where R^(1a) is benzothiopheneoptionally substituted with 1, 2, or 3 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(v), Formula I(v′), or Formula I(v″) is that where R^(1a) isaryl optionally substituted with 1, 2, or 3 R⁷ groups; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(v), Formula I(v′), or Formula I(v″) is that whereR^(1a) is phenyl optionally substituted with 1, 2, or 3 R⁷ groups; andall other groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(v), Formula I(v′), or FormulaI(v″) is that where at least one R⁷ is halo; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(v), Formula I(v′), or Formula I(v″) is that where R⁷ is phenylor heteroaryl optionally substituted with at least one R^(7a); and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(v), Formula I(v′), or FormulaI(v″) is that where at least one R^(7a) is halo; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(w), Formula I(w′), or Formula I(w″):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(w), Formula I(w′), or FormulaI(w″) is that where R² and R³ together with the nitrogen to which theyare attached form a 3-10 membered heterocycloalkyl ring which isoptionally substituted with 1, 2, or 3 R⁸; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(w), Formula I(w′), or Formula I(w″) is that where R⁴ isheteroaryl optionally substituted with 1, 2, or 3 R⁹ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(w), Formula I(w′), or FormulaI(w″) is that where R⁴ is unsubstituted2,3-dihydrobenzo[b][1,4]dioxinyl; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(w),Formula I(w′), or Formula I(w″) is that where R⁴ is aryl optionallysubstituted with 1, 2, or 3 R⁹ groups; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(w), Formula I(w′), or Formula I(w″) is that where at least oneR⁹ is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(w), Formula I(w′), orFormula I(w″) is that where at least one R⁹ is alkoxy; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(w), Formula I(w′), or Formula I(w″) is that whereR^(1a) is heteroaryl optionally substituted with 1, 2, or 3 R⁷ groups;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(w), Formula I(w′), or FormulaI(w″) is that where R^(1a) is benzofuranyl optionally substituted with1, 2, or 3 R⁷ groups; and all other groups are as defined in the Summaryof the Invention or as defined in any of the embodiments describedherein. In another embodiment, the compound of Formula I(w), FormulaI(w′), or Formula I(w″) is that where R^(1a) is benzothiopheneoptionally substituted with 1, 2, or 3 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(w), Formula I(w′), or Formula I(w″) is that where R^(1a) isaryl optionally substituted with 1, 2, or 3 R⁷ groups; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(w), Formula I(w′), or Formula I(w″) is that whereR^(1a) is phenyl optionally substituted with 1, 2, or 3 R⁷ groups; andall other groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(w), Formula I(w′), or FormulaI(w″) is that where at least one R⁷ is halo; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(w), Formula I(w′), or Formula I(w″) is that where R⁷ is phenylor heteroaryl optionally substituted with at least one R^(7a); and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(w), Formula I(w′), or FormulaI(w″) is that where at least one R^(7a) is halo; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(x), Formula I(x′), or Formula I(x″):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(x), Formula I(x′), or FormulaI(x″) is that where R² and R³ together with the nitrogen to which theyare attached form a 3-10 membered heterocycloalkyl ring which isoptionally substituted with 1, 2, or 3 R⁸; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(x), Formula I(x′), or Formula I(x″) is that where at least oneR⁹ is halo; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(x), Formula I(x′), orFormula I(x″) is that where at least one R⁹ is alkoxy; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(v), Formula I(v′), or Formula I(v″) is that wherethere are 2 R⁹ groups, where one R⁹ is halo and one R⁹ is alkoxy,preferably cyclopropyloxy; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(x),Formula I(x′), or Formula I(x″) is that where R^(1a) is heteroaryloptionally substituted with 1, 2, or 3 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(x), Formula I(x′), or Formula I(x″) is that where R^(1a) isbenzofuranyl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(x), Formula I(x′), or FormulaI(x″) is that where R^(1a) is benzothiophene optionally substituted with1, 2, or 3 R⁷ groups; and all other groups are as defined in the Summaryof the Invention or as defined in any of the embodiments describedherein. In another embodiment, the compound of Formula I(x), FormulaI(x′), or Formula I(x″) is that where R^(1a) is aryl optionallysubstituted with 1, 2, or 3 R⁷ groups; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(x), Formula I(x′), or Formula I(x″) is that where R^(1a) isphenyl optionally substituted with 1, 2, or 3 R⁷ groups; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(x), Formula I(x′), or Formula I(x″) is that whereat least one R⁷ is halo; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(x),Formula I(x′), or Formula I(x″) is that where R⁷ is phenyl or heteroaryloptionally substituted with at least one R^(7a); and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(x), Formula I(x′), or Formula I(x″) is that where at least oneR^(7a) is halo; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(y), Formula I(y′), or Formula I(y″):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(y), Formula I(y′), or FormulaI(y″) is that where at least one R⁹ is halo; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(y), Formula I(y′), or Formula I(y″) is that where at least oneR⁹ is alkoxy; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(v), Formula I(v′), orFormula I(v″) is that where there are 2 R⁹ groups, where one R⁹ is haloand one R⁹ is alkoxy, preferably cyclopropyloxy; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(y), Formula I(y′), or Formula I(y″) is that where R^(1a) isheteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(y), Formula I(y′), or FormulaI(y″) is that where R^(1a) is benzofuranyl optionally substituted with1, 2, or 3 R⁷ groups; and all other groups are as defined in the Summaryof the Invention or as defined in any of the embodiments describedherein. In another embodiment, the compound of Formula I(y), FormulaI(y′), or Formula I(y″) is that where R^(1a) is benzothiopheneoptionally substituted with 1, 2, or 3 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(y), Formula I(y′), or Formula I(y″) is that where R^(1a) isaryl optionally substituted with 1, 2, or 3 R⁷ groups; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(y), Formula I(y′), or Formula I(y″) is that whereR^(1a) is phenyl optionally substituted with 1, 2, or 3 R⁷ groups; andall other groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(y), Formula I(y′), or FormulaI(y″) is that where at least one R⁷ is halo; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(y), Formula I(y′), or Formula I(y″) is that where R⁷ is phenylor heteroaryl optionally substituted with at least one R^(7a); and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(y), Formula I(y′), or FormulaI(y″) is that where at least one R^(7a) is halo; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(z), Formula I(z′), or Formula I(z″):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(z), Formula I(z′), or FormulaI(z″) is that where at least one R⁹ is halo; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(z), Formula I(z′), or Formula I(z″) is that where at least oneR⁹ is alkoxy; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(v), Formula I(v′), orFormula I(v″) is that where there are 2 R⁹ groups, where one R⁹ is haloand one R⁹ is alkoxy, preferably cyclopropyloxy; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(z), Formula I(z′), or Formula I(z″) is that where R^(1a) isheteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(z), Formula I(z′), or FormulaI(z″) is that where R^(1a) is benzofuranyl optionally substituted with1, 2, or 3 R⁷ groups; and all other groups are as defined in the Summaryof the Invention or as defined in any of the embodiments describedherein. In another embodiment, the compound of Formula I(z), FormulaI(z′), or Formula I(z″) is that where R^(1a) is benzothiopheneoptionally substituted with 1, 2, or 3 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(z), Formula I(z′), or Formula I(z″) is that where R^(1a) isaryl optionally substituted with 1, 2, or 3 R⁷ groups; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(z), Formula I(z′), or Formula I(z″) is that whereR^(1a) is phenyl optionally substituted with 1, 2, or 3 R⁷ groups; andall other groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(z), Formula I(z′), or FormulaI(z″) is that where at least one R⁷ is halo; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein. In another embodiment, the compound ofFormula I(z), Formula I(z′), or Formula I(z″) is that where R⁷ is phenylor heteroaryl optionally substituted with at least one R^(7a); and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(z), Formula I(z′), or FormulaI(z″) is that where at least one R^(7a) is halo; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or FormulaI(ae):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac),Formula I(ad), or Formula I(ae) is that where R⁵ is OH; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(aa), Formula I(ab), Formula I(ac), Formula I(ad),or Formula I(ae) is that where R⁴ is heteroaryl optionally substitutedwith 1, 2, or 3 R⁹ groups; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(aa),Formula I(ab), Formula I(ac), Formula I(ad), or Formula I(ae) is thatwhere R⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups; andall other groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac),Formula I(ad), or Formula I(ae) is that where R² and R³ together withthe nitrogen to which they are attached form a 3-10 memberedheterocycloalkyl ring which is optionally substituted with 1, 2, or 3R⁸; and all other groups are as defined in the Summary of the Inventionor as defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac),Formula I(ad), or Formula I(ae) is that where R⁶ and R^(6a) are halo;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac),Formula I(ad), or Formula I(ae) is that where R^(1a) is heteroaryloptionally substituted with 1, 2, or 3 R⁷ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or FormulaI(ae) is that where at least one R⁷ is halo; and all other groups are asdefined in the Summary of the Invention or as defined in any of theembodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(af), Formula I(ag), Formula I(ah), Formula I(ai), FormulaI(aj), or Formula I(ak):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(af), Formula I(ag), Formula I(ah),Formula I(ai), Formula I(aj), or Formula I(ak) is that where X¹ isalkylene or alkenylene; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(af),Formula I(ag), Formula I(ah), Formula I(ai), Formula I(aj), or FormulaI(ak) is that where R⁵ is OH; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(af),Formula I(ag), Formula I(ah), Formula I(ai), Formula I(aj), or FormulaI(ak) is that where R⁴ is heteroaryl optionally substituted with 1, 2,or 3 R⁹ groups; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(af), Formula I(ag),Formula I(ah), Formula I(ai), Formula I(aj), or Formula I(ak) is thatwhere R⁴ is aryl optionally substituted with 1, 2, or 3 R⁹ groups; andall other groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(af) or Formula I(ai) is that whereR² and R³ together with the nitrogen to which they are attached form a3-10 membered heterocycloalkyl ring which is optionally substituted with1, 2, or 3 R⁸; and all other groups are as defined in the Summary of theInvention or as defined in any of the embodiments described herein. Inanother embodiment, the compound of Formula I(af), Formula I(ag), orFormula I(ah), is that where R⁶ and R^(6a) are halo; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(af), Formula I(ag), Formula I(ah), Formula I(ai),Formula I(aj), or Formula I(ak) is that where R^(1a) is aryl orheteroaryl optionally substituted with 1, 2, or 3 R⁷ groups; and allother groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(af), Formula I(ag), Formula I(ah),Formula I(ai), Formula I(aj), or Formula I(ak) is that where at leastone R⁷ is halo; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according toFormula I(al), Formula I(am), Formula I(an), or Formula I(ao):

where all groups are as defined in the Summary of the Invention or asdefined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(am) or Formula I(ao) is that whereX¹ is alkylene or alkenylene; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(al),Formula I(am), Formula I(an), or Formula I(ao) is that where R⁵ is OH;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein. In anotherembodiment, the compound of Formula I(al), Formula I(am), Formula I(an),or Formula I(ao) is that where R⁴ is heteroaryl optionally substitutedwith 1, 2, or 3 R⁹ groups; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(al),Formula I(am), Formula I(an), or Formula I(ao) is that where R⁴ is aryloptionally substituted with 1, 2, or 3 R⁹ groups; and all other groupsare as defined in the Summary of the Invention or as defined in any ofthe embodiments described herein. In another embodiment, the compound ofFormula I(al), Formula I(am), Formula I(an), or Formula I(ao) is thatwhere R² and R³ together with the nitrogen to which they are attachedform a 3-10 membered heterocycloalkyl ring which is optionallysubstituted with 1, 2, or 3 R⁸; and all other groups are as defined inthe Summary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(al)or Formula I(am) is that where R⁶ and R^(6a) are halo; and all othergroups are as defined in the Summary of the Invention or as defined inany of the embodiments described herein. In another embodiment, thecompound of Formula I(al), Formula I(am), Formula I(an), or FormulaI(ao) is that where R^(1a) is aryl or heteroaryl optionally substitutedwith 1, 2, or 3 R⁷ groups; and all other groups are as defined in theSummary of the Invention or as defined in any of the embodimentsdescribed herein. In another embodiment, the compound of Formula I(al),Formula I(am), Formula I(an), or Formula I(ao) is that where at leastone R⁷ is halo; and all other groups are as defined in the Summary ofthe Invention or as defined in any of the embodiments described herein.In another embodiment, the compound of Formula I(al), Formula I(am),Formula I(an), or Formula I(ao) is that where at least one R¹² is CH₃;and all other groups are as defined in the Summary of the Invention oras defined in any of the embodiments described herein.

In some or any embodiments, the compound is that of any one of Examples1-74.

In some or any embodiments, the compound is that of any one of Examples77-383.

In some or any embodiments, the compound is that of any one of Examples384-478.

In some or any embodiments, the compound is selected from Table 1.

In some or any embodiments, the compound is selected from Table 2.

In some or any embodiments, the compound is selected from Table 3.

In some or any embodiments, the compound is selected from Table 1, whereR^(1a) is aryl, which is optionally substituted with 1, 2, or 3 R⁷groups.

In some or any embodiments, the compound is selected from Table 1, whereR^(1a) is heterocycloalkyl, which is optionally substituted with 1, 2,or 3 R⁷ groups.

In some or any embodiments, the compound is selected from Table 1, whereR^(1a) is heteroaryl, which is optionally substituted with 1, 2, or 3 R⁷groups.

In some or any embodiments, the compound is selected from Table 1, whereR² and R³ together with the nitrogen to which they are attached form a4-5 membered monocyclic heterocycloalkyl ring, which is optionallysubstituted with 1 or 2 R⁸.

In some or any embodiments, the compound is selected from Table 1, whereR² and R³ together with the nitrogen to which they are attached form a7-8 membered bicyclic heterocycloalkyl ring, which is optionallysubstituted with 1 or 2 R⁸.

In some or any embodiments, the compound is selected from Table 1, whereR⁴ is aryl, which is optionally substituted with 1, 2, or 3 R⁹ groups.

In some or any embodiments, the compound is selected from Table 1, whereR⁴ is heteroaryl, which is optionally substituted with 1, 2, or 3 R⁹groups.

In some or any embodiments, the compound is selected from Table 1, whereR⁵ is —OH.

In some or any embodiments, the compound is selected from Table 1, whereR⁶ and R^(6a) together with the carbon to which they are attached formC(O).

In some or any embodiments, the compound is selected from Table 2, whereR^(1a) is heterocycloalkyl, which is optionally substituted with 1, 2,or 3 R⁷ groups.

In some or any embodiments, the compound is selected from Table 2, whereR^(1a) is heteroaryl, which is optionally substituted with 1, 2, or 3 R⁷groups.

In some or any embodiments, the compound is selected from Table 2, whereR² and R³ together with the nitrogen to which they are attached form a4-5 membered monocyclic heterocycloalkyl ring, which is optionallysubstituted with 1 or 2 R⁸.

In some or any embodiments, the compound is selected from Table 2, whereR² and R³ together with the nitrogen to which they are attached form a7-8 membered bicyclic heterocycloalkyl ring, which is optionallysubstituted with 1 or 2 R⁸.

In some or any embodiments, the compound is selected from Table 2, whereR⁴ is aryl, which is optionally substituted with 1, 2, or 3 R⁹ groups.

In some or any embodiments, the compound is selected from Table 2, whereR⁴ is heteroaryl, which is optionally substituted with 1, 2, or 3 R⁹groups.

In some or any embodiments, the compound is selected from Table 2, whereR⁵ is —OH.

In some or any embodiments, the compound is selected from Table 2, whereR⁶ and R^(6a) together with the carbon to which they are attached formC(O).

In some or any embodiments, the compound is selected from Table 3, whereR^(1a) is heterocycloalkyl, which is optionally substituted with 1, 2,or 3 R⁷ groups.

In some or any embodiments, the compound is selected from Table 3, whereR^(1a) is heteroaryl, which is optionally substituted with 1, 2, or 3 R⁷groups.

In some or any embodiments, the compound is selected from Table 3, whereR² and R³ together with the nitrogen to which they are attached form a4-5 membered monocyclic heterocycloalkyl ring, which is optionallysubstituted with 1 or 2 R⁸.

In some or any embodiments, the compound is selected from Table 3, whereR² and R³ together with the nitrogen to which they are attached form a7-8 membered bicyclic heterocycloalkyl ring, which is optionallysubstituted with 1 or 2 R⁸.

In some or any embodiments, the compound is selected from Table 3, whereR⁴ is aryl, which is optionally substituted with 1, 2, or 3 R⁹ groups.

In some or any embodiments, the compound is selected from Table 3, whereR⁴ is heteroaryl, which is optionally substituted with 1, 2, or 3 R⁹groups.

In some or any embodiments, the compound is selected from Table 3, whereR⁵ is —OH.

In some or any embodiments, the compound is selected from Table 3, whereR⁶ and R^(6a) together with the carbon to which they are attached formC(O).

In some or any embodiments, provided is a pharmaceutical compositioncomprising 1) a Compound of Formula I, I(a), I(b), I(c), I(d), I(e),I(f), I(g), I(h), I(j), I(k), I(m), I(n), I(p), I(q), I(r), I(s), I(t),I(u), I(v), I(v′), I(v″), I(w), I(w′), I(w″), I(x), I(x′), I(x″), I(y),I(y′), I(y″), I(z), I(z′), I(z″), I(aa), I(ab), I(ac), I(ad), I(ae),I(af), I(ag), I(ah), I(ai), I(aj), I(ak), I(al), I(am), I(an), or I(ao)or a compound in Table 1, 2, or 3, optionally as a tautomer, a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof, and 2) apharmaceutically acceptable excipient or pharmaceutically acceptablecarrier.

Pharmaceutical Composition/Formulation

In some or any embodiments, optionally in combination with any or all ofthe above various embodiments, provided herein is a pharmaceuticalcomposition comprising of a compound of Formula I, I(a), I(b), I(c),I(d), I(e), I(f), I(g), I(h), I(j), I(k), I(m), I(n), I(p), I(q), I(r),I(s), I(t), I(u), I(v), I(v′), I(v″), I(w), I(w′), I(w″), I(x), I(x′),I(x″), I(y), I(y′), I(y″), I(z), I(z′), I(z″), I(aa), I(ab), I(ac),I(ad), I(ae), I(af), I(ag), I(ah), I(ai), I(aj), I(ak), I(al), I(am),I(an), or I(ao), or a compound of Table 1, 2, or 3, or stereoisomers, ora pharmaceutically acceptable salt, and one or more pharmaceuticallyacceptable carrier(s), excipient(s), binder(s) or diluent(s). Thepharmaceutical compositions can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,coating agents or antioxidants.

In some or any embodiments, disclosed herein is a pharmaceuticalcomposition comprising a compound, pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate of any of the compounds disclosed herein. In some embodiments,the pharmaceutical compositions further comprises a pharmaceuticallyacceptable diluent, excipient or binder.

In some or any embodiments, pharmaceutical compositions are formulatedin any manner, including using one or more physiologically acceptablecarriers comprising excipients and/or auxiliaries which facilitateprocessing of the active compounds into pharmaceutical preparations. Insome embodiments, proper formulation is dependent upon the route ofadministration chosen. In various embodiments, any techniques, carriers,and excipients are used as suitable.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. In some or any embodiments, apharmaceutical composition facilitates administration of the compound toan organism. In some embodiments, practicing the methods of treatment oruse provided herein, includes administering or using a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundprovided herein. In specific embodiments, the methods of treatmentprovided for herein include administering such a pharmaceuticalcomposition to a mammal having a disease or condition to be treated. Inone embodiment, the mammal is a human. In some embodiments, thetherapeutically effective amount varies widely depending on the severityof the disease, the age and relative health of the subject, the potencyof the compound used and other factors. In various embodiments, thecompounds described herein are used singly or in combination with one ormore therapeutic agents as components of mixtures.

In a some or any embodiment, it is provided a method of forming acomposition, comprising providing a compound and forming thecomposition. In some embodiments, the composition further comprises apharmaceutically acceptable carrier. In some embodiments of thecomposition, optionally in combination with any or all of the abovevarious embodiments, the composition is formulated in a formulation forlocal or systemic delivery. Examples of such formulations areformulations for oral administration, injection, topical administration,pulmonary administration, or implant. In some or any embodiments, thecompound is according to any of the various embodiments described aboveor below.

In some or any embodiments, the pharmaceutical compositions providedherein are formulated for intravenous injections. In certain aspects,the intravenous injection formulations provided herein are formulated asaqueous solutions, and, in some embodiments, in physiologicallycompatible buffers such as Hank's solution, Ringer's solution, orphysiological saline buffer. In certain embodiments, the pharmaceuticalcompositions provided herein are formulated for transmucosaladministration. In some aspects, transmucosal formulations includepenetrants appropriate to the barrier to be permeated. In certainembodiments, the pharmaceutical compositions provided herein areformulated for other parenteral injections, appropriate formulationsinclude aqueous or nonaqueous solutions, and in one embodiment, withphysiologically compatible buffers or excipients.

In some or any embodiments, the pharmaceutical compositions providedherein are formulated for oral administration. In certain aspects, theoral formulations provided herein comprise compounds described hereinthat are formulated with pharmaceutically acceptable carriers orexcipients. Such carriers enable the compounds described herein to beformulated as tablets, powders, pills, dragees, capsules, liquids, gels,syrups, elixirs, slurries, suspensions and the like, for oral ingestionby a patient to be treated.

In some or any embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients include, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.I(f) desired, disintegrating agents are optionally added, such as thecross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, oralginic acid or a salt thereof such as sodium alginate.

In some or any embodiments, provided herein is a pharmaceuticalcomposition formulated as dragee cores with suitable coatings. In someor any embodiments, concentrated sugar solutions are used in forming thesuitable coating, and optionally contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. In some embodiments, dyestuffs and/or pigments are added totablets, dragees and/or the coatings thereof for, e.g., identificationor to characterize different combinations of active compound doses.

In some or any embodiments, pharmaceutical preparations which are usedinclude orally include push-fit capsules made of gelatin, as well assoft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. In some embodiments, the push-fit capsules containthe active ingredients in admixture with filler such as lactose, binderssuch as starches, and/or lubricants such as talc or magnesium stearateand, optionally, stabilizers. In some or any embodiments, in softcapsules, the active compounds are dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers are optionally added. In some or anyembodiments, the formulations for oral administration are in dosagessuitable for such administration.

In some or any embodiments, the pharmaceutical compositions providedherein are formulated for buccal or sublingual administration. In someor any embodiments, buccal or sublingual compositions take the form oftablets, lozenges, or gels formulated in a conventional manner. In someor any embodiments, parenteral injections involve bolus injection orcontinuous infusion. In some embodiments, formulations for injection arepresented in unit dosage form, e.g., in ampoules or in multi-dosecontainers, with an added preservative. In some embodiments, thepharmaceutical composition described herein is in a form suitable forparenteral injection as a sterile suspensions, solutions or emulsions inoily or aqueous vehicles, and optionally contains formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. In some embodiments,suspensions of the active compounds are prepared as appropriate oilyinjection suspensions. Suitable lipophilic solvents or vehicles includefatty oils such as sesame oil, or synthetic fatty acid esters, such asethyl oleate or triglycerides, or liposomes. In some or any embodiments,aqueous injection suspensions contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspensions also contain suitablestabilizers or agents which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions. Inalternative embodiments, the active ingredient is in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In some embodiments, the compounds described herein are administeredtopically. In specific embodiments, the compounds described herein areformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compounds optionallycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand/or preservatives.

In some or any embodiments, the pharmaceutical compositions providedherein are formulated for transdermal administration of compoundsdescribed herein. In some embodiments, administration of suchcompositions employs transdermal delivery devices and transdermaldelivery patches. In some or any embodiments, the compositions arelipophilic emulsions or buffered, aqueous solutions, dissolved and/ordispersed in a polymer or an adhesive. Such patches include thoseconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents. In some embodiments, transdermal delivery of thecompounds described herein is accomplished by use of iontophoreticpatches and the like. In some or any embodiments, transdermal patchesprovide controlled delivery of the compounds provided herein, such as,for example, compounds of Formula (I). In some or any embodiments, therate of absorption is slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. Conversely,absorption enhancers are optionally used to increase absorption.Absorption enhancer and carrier include absorbable pharmaceuticallyacceptable solvents that assist in passage of the compound through theskin. For example, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

In some or any embodiments, the pharmaceutical compositions providedherein are formulated for administration by inhalation. In some or anyembodiments, in such pharmaceutical compositions formulated forinhalation, the compounds described herein are in a form as an aerosol,a mist or a powder. In some embodiments, pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In certain aspects of a pressurized aerosol, thedosage unit is determined by providing a valve to deliver a meteredamount. In some or any embodiments, capsules and cartridges of, such as,by way of example only, gelatin for use in an inhaler or insufflator isformulated containing a powder mix of the compound described herein anda suitable powder base such as lactose or starch.

In some embodiments, the compounds described herein are formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas. Insome or any embodiments, rectal compositions optionally containconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In some or any suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter is first melted.

In various embodiments provided herein, the pharmaceutical compositionsare formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopharmaceutically acceptable preparations. In some or any embodiments,proper formulation is dependent upon the route of administration chosen.In various embodiments, any of the techniques, carriers, and excipientsis used as suitable. In some embodiments, pharmaceutical compositionscomprising a compound described herein are manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

In some or any embodiments, the pharmaceutical compositions include atleast one pharmaceutically acceptable carrier, diluent or excipient anda compound described herein described herein as an active ingredient infree-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity. In some situations, compounds described hereinexist as tautomers. All tautomers are included within the scope of thecompounds presented herein. Additionally, included herein are thesolvated and unsolvated forms of the compounds described herein.Solvated compounds include those that are solvated with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein. In some embodiments, the pharmaceutical compositionsdescribed herein include other medicinal or pharmaceutical agents,carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, and/or buffers. In additional embodiments, the pharmaceuticalcompositions described herein also contain other therapeuticallyvaluable substances.

Methods for the preparation of compositions containing the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. In various embodiments, thecompositions are in liquid solutions or suspensions, solid formssuitable for solution or suspension in a liquid prior to use, or asemulsions. These compositions optionally contain minor amounts ofnontoxic, auxiliary substances, such as wetting or emulsifying agents,pH buffering agents, and so forth.

In some embodiments, a composition comprising a compound describedherein takes the form of a liquid where the agents are present insolution, in suspension or both. In some embodiments, when thecomposition is administered as a solution or suspension a first portionof the agent is present in solution and a second portion of the agent ispresent in particulate form, in suspension in a liquid matrix. In someembodiments, a liquid composition includes a gel formulation. In otherembodiments, the liquid composition is aqueous.

Useful aqueous suspension optionally contain one or more polymers assuspending agents. Useful polymers include water-soluble polymers suchas cellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Useful compositions optionally comprise an mucoadhesivepolymer, selected for example from carboxymethylcellulose, carbomer(acrylic acid polymer), poly(methylmethacrylate), polyacrylamide,polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginateand dextran.

Useful compositions optionally include solubilizing agents to aid in thesolubility of a compound described herein. The term “solubilizing agent”generally includes agents that result in formation of a micellarsolution or a true solution of the agent. Solubilizing agents includecertain acceptable nonionic surfactants, for example polysorbate 80, andophthalmically acceptable glycols, polyglycols, e.g., polyethyleneglycol 400, and glycol ethers.

Useful compositions optionally include one or more pH adjusting agentsor buffering agents, including acids such as acetic, boric, citric,lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, sodium lactate and tris-hydroxymethylaminomethane; and bufferssuch as citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an acceptable range.

Useful compositions optionally include one or more salts in an amountrequired to bring osmolality of the composition into an acceptablerange. Such salts include those having sodium, potassium or ammoniumcations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Certain useful compositions optionally include one or more preservativesto inhibit microbial activity. Suitable preservatives includemercury-containing substances such as merfen and thiomersal; stabilizedchlorine dioxide; and quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Some useful compositions optionally include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Certain useful compositions optionally one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In some embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. In alternative embodiments,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition.

In various embodiments, any delivery system for hydrophobicpharmaceutical compounds is employed. Liposomes and emulsions areexamples of delivery vehicles or carriers for hydrophobic drugs. In someor any embodiments, certain organic solvents such as N-methylpyrrolidoneare employed. In some embodiments, the compounds are delivered using asustained-release system, such as semipermeable matrices of solidhydrophobic polymers containing the therapeutic agent. Varioussustained-release materials are utilized in the embodiments herein. Insome or any embodiments, sustained-release capsules release thecompounds for a few weeks up to over 100 days. In some embodiments,depending on the chemical nature and the biological stability of thetherapeutic reagent, additional strategies for protein stabilization areemployed.

In some or any embodiments, the formulations or compositions describedherein benefit from and/or optionally comprise antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

In some or any embodiments, the method can be conducted in living bodiesof mammals. In such a case, the compounds may be administered to themammals.

In some or any embodiments, the compounds described herein are used inthe preparation or manufacture of medicaments for the treatment ofdiseases or conditions that are mediated by the enzyme GCS or in whichinhibition of the enzyme GCS ameliorates the disease or condition. Insome embodiments, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, pharmaceutically acceptable N-oxide, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject.

In some or any embodiments, provided is a method of treating orameliorating a medical condition, comprising administering to a subjectin need thereof a compound according to any of the various embodimentsdescribed herein or a pharmaceutical composition according to any of thevarious embodiments described herein.

In some or any embodiments, provided herein is a method of treating orameliorating a disease ameliorated by the inhibition of GCS comprisingadministering to a subject in need of treatment atherapeutically-effective amount of a compound of Formula I, I(a), I(b),I(c), I(d), I(e), I(f), I(g), I(h), I(j), I(k), I(m), I(n), I(p), I(q),I(r), I(s), I(t), I(u), I(v), I(v′), I(v″), I(w), I(w′), I(w″), I(x),I(x′), I(x″), I(y), I(y′), I(y″), I(z), I(z′), I(z″), I(aa), I(ab),I(ac), I(ad), I(ae), I(af), I(ag), I(ah), I(ai), I(aj), I(ak), I(al),I(am), I(an), or I(ao), or a compound in Table 1, 2, or 3, optionally asa tautomer, a single stereoisomer or mixture of stereoisomers thereofand additionally optionally as a pharmaceutically acceptable saltthereof. In some or any embodiments, the disease is selected fromglycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GM1gangliosidosis and Fabry diseases); diseases associated with glycolipidaccumulation (e.g., Gaucher disease); diseases that cause renalhypertrophy or hyperplasia such as diabetic nephropathy; diseases thatcause hyperglycemia or hyperinsulemia; cancers in which glycolipidsynthesis is abnormal; infectious diseases caused by organisms which usecell surface glycolipids as receptors or in which synthesis ofglucosylceramide is essential or important; a metabolic disorder such asatherosclerosis, polycystic kidney disease, renal hypertrophy, diabetesmellitus, and obesity; cancer such as breast cancer, renaladenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinalcancer, pancreas and prostrate cancer; neuronal disorders; neuronalinjury; inflammatory diseases or disorders (e.g., rheumatoid arthritis,Crohn's disease, asthma and sepsis), and diabetes mellitus and obesity

In any of the aforementioned embodiments are further embodiments thatinclude single administrations of the effective amount of the compound,including further embodiments in which the compound is administered tothe subject (i) once; (ii) multiple times over the span of one day;(iii) continually; or (iv) continuously.

In any of the aforementioned embodiments are further embodiments inwhich administration is enteral, parenteral, or both, and wherein:

-   -   (a) the effective amount of the compound is systemically        administered to the subject;    -   (b) the effective amount of the compound is administered orally        to the subject;    -   (c) the effective amount of the compound is intravenously        administered to the subject;    -   (d) the effective amount of the compound administered by        inhalation;    -   (e) the effective amount of the compound is administered by        nasal administration;    -   (f) the effective amount of the compound is administered by        injection to the subject;    -   (g) the effective amount of the compound is administered        topically (dermal) to the subject;    -   (h) the effective amount of the compound is administered by        ophthalmic administration; and/or    -   (i) the effective amount of the compound is administered        rectally to the subject.

In some or any embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In some or any therapeutic applications, the compositionsare administered to a patient already suffering from a disease orcondition, in an amount sufficient to cure or at least partially arrestthe symptoms of the disease or condition. In some embodiments, amountseffective for this use will depend on the severity and course of thedisease or condition, previous therapy, the patient's health status,weight, and response to the drugs, and the judgment of the treatingphysician. In certain instances, it is considered appropriate for thecaregiver to determine such therapeutically effective amounts by routineexperimentation (including, but not limited to, a dose escalationclinical trial).

In some or any prophylactic applications, compositions containing thecompounds described herein are administered to a patient susceptible toor otherwise at risk of a particular disease, disorder or condition. Insome embodiments, the amount administered is defined to be a“prophylactically effective amount or dose.” In some or any embodimentsof this use, the precise amounts of compound administered depend on thepatient's state of health, weight, and the like. In some embodiments, itis considered appropriate for the caregiver to determine suchprophylactically effective amounts by routine experimentation (e.g., adose escalation clinical trial). In some or any embodiments, when usedin a patient, effective amounts for this use will depend on the severityand course of the disease, disorder or condition, previous therapy, thepatient's health status and response to the drugs, and the judgment ofthe treating physician.

In some or any embodiments are further embodiments that include multipleadministrations of the effective amount of the compound, includingfurther embodiments wherein:

(i) the compound is administered in a single dose;

(ii) the time between multiple administrations is every 6 hours;

(iii) the compound is administered to the subject every 8 hours.

In further or alternative embodiments, the method includes a drugholiday, wherein the administration of the compound is temporarilysuspended or the dose of the compound being administered is temporarilyreduced; at the end of the drug holiday, dosing of the compound isresumed. In some embodiments, the length of the drug holiday varies from2 days to 1 year.

In certain instances, a patient's condition does not improve or does notsignificantly improve following administration of a compound orcomposition described herein and, upon the doctor's discretion theadministration of the compounds is optionally administered chronically,that is, for an extended period of time, including throughout theduration of the patient's life in order to ameliorate or otherwisecontrol or limit the symptoms of the patient's disease or condition.

In certain cases wherein the patient's status does improve or does notsubstantially improve, upon the doctor's discretion the administrationof the compounds are optionally given continuously; alternatively, thedose of drug being administered is optionally temporarily reduced ortemporarily suspended for a certain length of time (i.e., a “drugholiday”). In some or any embodiments, the length of the drug holidayvaries between 2 days and 1 year, including by way of example only, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days,20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350days, or 365 days. The dose reduction during a drug holiday includes areduction from about 10% to about 100%, including, by way of exampleonly, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about100%.

In some or any embodiments, once improvement of the patient's conditionshas occurred, a maintenance dose is administered if necessary. In someembodiments, the dosage, e.g., of the maintenance dose, or the frequencyof administration, or both, are reduced, as a function of the symptoms,to a level at which the improved disease, disorder or condition isretained. In some or any embodiments, however, patients are optionallygiven intermittent treatment on a long-term basis upon any recurrence ofsymptoms.

In some or any embodiments, the amount of a given agent that correspondsto an effective amount varies depending upon factors such as theparticular compound, disease or condition and its severity, the identity(e.g., weight) of the subject or host in need of treatment. In someembodiments, the effective amount is, nevertheless, determined accordingto the particular circumstances surrounding the case, including, e.g.,the specific agent that is administered, the route of administration,the condition being treated, and the subject or host being treated. Insome or any embodiments, however, doses employed for adult humantreatment is in the range of about 0.02 to about 5000 mg per day, in aspecific embodiment about 1 to about 1500 mg per day. In variousembodiments, the desired dose is conveniently presented in a single doseor as divided doses administered simultaneously (or over a short periodof time) or at appropriate intervals, for example as two, three, four ormore sub-doses per day.

In some or any embodiments, the pharmaceutical compositions describedherein are in a unit dosage form suitable for single administration ofprecise dosages. In some instances, in unit dosage form, the formulationis divided into unit doses containing appropriate quantities of one ormore compound. In some or any embodiments, the unit dosage is in theform of a package containing discrete quantities of the formulation.Non-limiting examples are packaged tablets or capsules, and powders invials or ampoules. In some embodiments, aqueous suspension compositionsare packaged in single-dose non-reclosable containers. In alternativeembodiments, multiple-dose reclosable containers are used, in which caseit is typical to include a preservative in the composition. By way ofexample only, formulations for parenteral injection are, in someembodiments, presented in unit dosage form, which include, but are notlimited to ampoules, or in multi-dose containers, with an addedpreservative.

In some or any embodiments, the daily dosages appropriate for thecompounds described herein described herein are from about 0.01 to about2.5 mg/kg per body weight. In some embodiments, an indicated dailydosage in the larger subject, including, but not limited to, humans, isin the range from about 0.5 mg to about 100 mg, convenientlyadministered in divided doses, including, but not limited to, up to fourtimes a day or in extended release form. In some or any embodiments,suitable unit dosage forms for oral administration comprise from about 1to about 50 mg active ingredient. The foregoing ranges are merelysuggestive, as the number of variables in regard to an individualtreatment regime is large, and considerable excursions from theserecommended values are not uncommon. In some or any embodiments, thedosages are altered depending on a number of variables, not limited tothe activity of the compound used, the disease or condition to betreated, the mode of administration, the requirements of the individualsubject, the severity of the disease or condition being treated, and thejudgment of the practitioner.

In some or any embodiments, toxicity and therapeutic efficacy of suchtherapeutic regimens are determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, including, but notlimited to, the determination of the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between the toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratiobetween LD₅₀ and ED₅₀. In some or any embodiments, compounds exhibitinghigh therapeutic indices are preferred. In some embodiments, the dataobtained from cell culture assays and animal studies is used informulating a range of dosage for use in human. In specific embodiments,the dosage of such compounds lies within a range of circulatingconcentrations that include the ED₅₀ with minimal toxicity. In some orany embodiments, the dosage varies within this range depending upon thedosage form employed and the route of administration utilized.

Kits/Articles of Manufacture

Articles of manufacture, comprising packaging material, a compoundprovided herein that is effective for modulating the activity of theenzyme GCS, or for treatment, prevention or amelioration of one or moresymptoms of a GCS-mediated disease or condition, within the packagingmaterial, and a label that indicates that the compound or composition,or pharmaceutically acceptable salt, pharmaceutically acceptableN-oxide, pharmaceutically active metabolite, pharmaceutically acceptableprodrug, or pharmaceutically acceptable solvate thereof, is used formodulating the activity of GCS, or for treatment, prevention oramelioration of one or more symptoms of GCS-mediated disease orcondition, are provided.

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. In variousembodiments, such kits comprise a carrier, package, or container that iscompartmentalized to receive one or more containers such as vials,tubes, and the like, each of the container(s) comprising one of theseparate elements to be used in a method described herein. Suitablecontainers include, for example, bottles, vials, syringes, and testtubes. In some embodiments, the containers are formed from a variety ofmaterials such as glass or plastic.

In some embodiments, the articles of manufacture provided herein containpackaging materials. Packaging materials for use in packagingpharmaceutical products include, but are not limited to, blister packs,bottles, tubes, inhalers, pumps, bags, vials, containers, syringes,bottles, and any packaging material suitable for a selected formulationand intended mode of administration and treatment.

In some embodiments, the container(s) described herein comprise one ormore compounds described herein, optionally in a composition or incombination with another agent as disclosed herein. The container(s)optionally have a sterile access port (for example in some embodimentsthe container is an intravenous solution bag or a vial having a stopperpierceable by a hypodermic injection needle). Such kits optionallycomprise a compound with an identifying description or label orinstructions relating to its use in the methods described herein.

In some embodiments, a kit will comprises one or more additionalcontainers, each with one or more of various materials (such asreagents, optionally in concentrated form, and/or devices) desirablefrom a commercial and user standpoint for use of a compound describedherein. Non-limiting examples of such materials include, but are notlimited to, buffers, diluents, filters, needles, syringes; carrier,package, container, vial and/or tube labels listing contents and/orinstructions for use, and package inserts with instructions for use. Aset of instructions is optionally included.

In some or any embodiments, a label is on or associated with thecontainer. In some embodiments, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself; a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In some or any embodiments, alabel indicates that the contents are to be used for a specifictherapeutic application. In some embodiments, the label indicatesdirections for use of the contents, such as in the methods describedherein.

In some or any embodiments, the pharmaceutical compositions arepresented in a pack or dispenser device which contains one or more unitdosage forms containing a compound provided herein. In some embodiments,the pack contains a metal or plastic foil, such as a blister pack. Thepack or dispenser device is optionally accompanied by instructions foradministration. In some embodiments, the pack or dispenser isaccompanied with a notice associated with the container in formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the drug for human or veterinary administration.In some or any embodiments, such notice is, for example, the labelingapproved by the U.S. Food and Drug Administration for prescriptiondrugs, or the approved product insert. In some embodiments, compositionscontaining a compound provided herein are formulated in a compatiblepharmaceutical carrier and are placed in an appropriate containerlabeled for treatment of an indicated condition.

Any combination of the groups described above for the various variablesis contemplated herein.

Preparation of Compounds

The following are illustrative examples of how the compounds can beprepared and tested. Although the examples can represent only someembodiments, it should be understood that the following examples areillustrative and not limiting.

In a further aspect, it is provided a method of making a compound,comprising synthesizing a compound as any of the various embodimentsdescribed above or below. Examples of the method are further describedin the Examples.

Compounds disclosed herein are commercially available or can be readilyprepared from commercially available starting materials according toestablished methodology in the art of organic synthesis. General methodsof synthesizing the compound can be found in, e.g., Stuart Warren andPaul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach,second Edition, Wiley, 2010. Synthesis of some of the compounds areexemplified in detail below.

In some embodiments, individual stereoisomers of compounds are preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution. These methods of resolution areexemplified by (1) attachment of a mixture of enantiomers to a chiralaxillary, separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary or (2) direct separation of the mixture ofoptical enantiomers on chiral chromatographic column.

Materials were obtained from commercial suppliers and were used withoutfurther purification. Air or moisture sensitive reactions were conductedunder argon atmosphere using oven-dried glassware and standardsyringe/septa techniques. ¹H NMR spectra were measured at 400 MHz unlessstated otherwise and data were reported as follows in ppm (δ) from theinternal standard (TMS, 0.0 ppm): chemical shift (multiplicity,integration, coupling constant in Hz).

A Compound of Formula I(h) (where all groups are as defined in theSummary of the Invention for a compound of Formula I or according to anyof the embodiments disclosed herein) can be prepared according toGeneral Scheme 1.

A Compound of Formula I(h) can be prepared using standard amide couplingconditions. More specifically, an intermediate of formula 100, which canbe prepared using procedures disclosed herein or are known to one ofordinary skill in the art, is treated with in a solvent such as DMF, DCMor THF, optionally in the presence of a base such as DIPEA or TEA, andin the presence of a coupling agent such as EDCI and/or HOBt to yield acompound of Formula I(h). The mixture can optionally be purified usingprocedures known to one of ordinary skill in the art. Alternatively, theintermediate of formula R¹C(O)OH can be treated with a chlorinatingagent such as oxalyl chloride in a solvent such as DMF followed bytreatment with the intermediate of formula 100 to yield a compound ofFormula I(h). The mixture can optionally be purified using proceduresknown to one of ordinary skill in the art.

A Compound of Formula I(j) (where all groups are as defined in theSummary of the Invention for a compound of Formula I or according to anyof the embodiments disclosed herein) can be prepared according toGeneral Scheme 2. A Compound of Formula I(h) is treated with a base suchas NMP, in the presence of NHCO₃, and in a solvent such as DCM to yielda Compound of Formula I(j).

A Compound of Formula I(k) or I(m) (where all groups are as defined inthe Summary of the Invention for a compound of Formula I or according toany of the embodiments disclosed herein) can be prepared according toGeneral Scheme 3. A Compound of Formula I(h) is treated with achlorinating agent such as SOCl₂ in a solvent such as DCM to yield aCompound of Formula I(k). A Compound of Formula I(m) is prepared bytreating a Compound of Formula I(k) with NH₂OCH₃ in a solvent such asMeOH.

A Compound of Formula I(n) (where all groups are as defined in theSummary of the Invention for a compound of Formula I or according to anyof the embodiments disclosed herein) can be prepared according toGeneral Scheme 4. A Compound of Formula I(j) is treated withhydroxylamine in a solvent such as MeOH to yield a Compound of FormulaI(n).

A Compound of Formula I(p) (where all groups are as defined in theSummary of the Invention for a compound of Formula I or according to anyof the embodiments disclosed herein) can be prepared according toGeneral Scheme 5. A Compound of Formula I(j) is treated with NaBD₄ in adeuterated solvent such as CD₃OD to yield a Compound of Formula I(p).

A Compound of Formula I(q) or I(r) (where all groups are as defined inthe Summary of the Invention for a compound of Formula I or according toany of the embodiments disclosed herein) can be prepared according toGeneral Scheme 6. A Compound of Formula I(k) is treated with NaN₃ in asolvent such as DMF and heated to about 50° C. to yield a Compound ofFormula I(q) which can be optionally worked up before proceeding to thenext step. The Compound of Formula I(q) is then treated with PPh₃ in asolvent such as THF to yield the Compound of Formula I(r).

In some or any embodiments of General Schemes 1-6, intermediate offormula 100 or the Compound of Formula I(h), I(j), or I(k) is that whereR² and R³ together with the nitrogen to which they are attached form a3-10-membered ring which is optionally substituted with 1, 2, or 3 R⁸groups.

A Compound of Formula I(s) (where R⁵ is hydroxy and R^(5a) is hydrogenand all groups are as defined in the Summary of the Invention for acompound of Formula I or according to any of the embodiments disclosedherein) can be prepared according to General Scheme 7.

An intermediate of formula 100b can be prepared using standard amidecoupling conditions. More specifically, an intermediate of formula 100a,which can be prepared using procedures disclosed herein or are known toone of ordinary skill in the art, is treated with in a solvent such asDMF, DCM or THF, optionally in the presence of a base such as DIPEA orTEA, and in the presence of a coupling agent such as EDCI and/or HOBt toyield an intermediate of formula 100c (e.g., a compound of Formula I(s)where R⁵ is —OTBS and R^(5a) is hydrogen). The protecting group inintermediate of formula 100c is then removed in the presence of TBAF ina solvent such as THF. The mixture can optionally be purified usingprocedures known to one of ordinary skill in the art. Alternatively, aCompound of Formula I(s) (where R⁵ is hydroxy and R^(5a) is hydrogen andall groups are as defined in the Summary of the Invention for a compoundof Formula I or according to any of the embodiments disclosed herein)can be prepared by treating an intermediate of formula 100a withR^(1a)C(O)C(O)OH using standard amide coupling procedures describedherein or known to one of ordinary skill in the art. The mixture canoptionally be purified using procedures known to one of ordinary skillin the art.

A Compound of Formula I(u) (where R⁵ is hydroxy and R^(5a) is hydrogenand all groups are as defined in the Summary of the Invention for acompound of Formula I or according to any of the embodiments disclosedherein) can be prepared according to General Scheme 7. The intermediateof formula 100c is treated with an intermediate of formula R^(1a)ONH₂ inthe presence of sodium acetate in a solvent such as ethanol or methanolto yield an intermediate of formula 100d (e.g., a compound of FormulaI(u) where R⁵ is —OTBS and R^(5a) is hydrogen and all groups are asdefined in the Summary of the Invention for a compound of Formula I oraccording to any of the embodiments disclosed herein). The intermediateof formula 100d is treated with TBAF in a solvent such as THF to yield aCompound of Formula I(u). The mixture can optionally be purified usingprocedures known to one of ordinary skill in the art. Alternatively, theCompound of Formula I(s) (where R⁵ is hydroxy and R^(5a) is hydrogen andall groups are as defined in the Summary of the Invention for a compoundof Formula I or according to any of the embodiments disclosed herein) istreated with an intermediate of formula R^(1a)ONH₂ in a solvent such asethanol or methanol to yield a Compound of Formula I(u). The mixture canoptionally be purified using procedures known to one of ordinary skillin the art.

Synthetic Examples

Benzyl chloroformate (50 mL, 50 w.t. % solution in toluene, 148 mmol)was added to a solution of (R)-2-amino-3-hydroxypropanoic acid (A1)(10.5 g, 100 mmol) in sat. aq NaHCO₃ solution (400 mL). The mixture wasstirred vigorously for 4 h at 20° C., and the aqueous solution wasextracted with ether (400 mL×2). The aqueous phase was acidified withconc. hydrochloric acid to pH=2 and extracted with ethyl acetate (300mL×3). The combined organic phase was dried with Na₂SO₄ and concentratedto afford crude product Compound A2 (20 g, yield 84%) as a white solid.LC-MS (m/z): 240 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) peaks: δ (ppm) 3.653(m, 2H), 4.051 (m, 1H), 4.884 (m, 1H), 5.038 (s, 2H), 7.303-7.373 (m,6H), 12.658 (s, 1H).

To a mixture of EDCI.HCl (2.4 g, 12.5 mmol), HOBt (1.7 g, 12.5 mmol),DIPEA (2.7 g, 20 mmol) in DCM (50 mL) was added Compound A2 (1 g, 4mmol) and N,O-dimethylhydroxylamine hydrochloride (1.2 g, 12.5 mmol).The mixture was stirred at rt overnight. The mixture was washed withhydrochloric acid solution (1 M, 50 mL×2), saturated aqueous NaHCO₃ (20mL), brine (20 mL), and dried over Na₂SO₄. The crude product waspurified by silica gel column chromatography (ethyl acetate inpetroleum, 30% v/v) to give Compound A3 (826 mg, yield 70%) as acolorless liquid. LC-MS (m/z): 283 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz)peaks: δ (ppm) 3.113 (s, 3H), 3.673 (s, 3H), 3.743 (t, J=4.8 Hz, 2H),4.766 (m, 1H), 4.959-5.044 (m, 2H), 6.046 (d, J=8.0 Hz, 1H), 7.200-7.254(m 5H).

TBDMS-Cl (800 mg, 5.31 mmol) in THF (10 mL) was added dropwise to asolution of Compound A3 (500 mg, 1.77 mmol) and imidazole (602 mg, 8.86mmol) in THF (20 mL) at 0° C. The mixture was stirred at rt for 2 h, andthen filtered. The filtrate was washed with 1N HCl (50 mL×2) and brine(50 mL), and dried over Na₂SO₄. The crude product was purified withsilica gel column chromatography (ethyl acetate in petroleum, 13% v/v)to give Compound A4 (526 mg, yield 75%) as a colorless liquid. LC-MS(m/z): 396 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) peaks: δ (ppm) 0.012 (s, 3H),0.085 (s, 6H), 0.852 (s, 9H), 3.211 (s, 3H), 3.756 (s, 3H), 3.794-3.896(m, 2H), 4.809 (m, 1H), 5.085 (q, J=11.2 Hz, 2H), 5.662 (d, J=8.8 Hz,1H), 7.286-7.351 (m 5H).

To a solution of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (4.9 g, 23mmol) in THF (100 mL) was added n-BuLi (1.6 M, 15 mL) at −60° C. underN₂ and stirred for 0.5 h, before a solution of Compound A4 (3 g, 7.6mmol) in THF (50 mL) was added slowly. The mixture was stirred at −60°C. for 1 h, and followed by addition of a saturate NH₄Cl solution. Themixture was extracted with ethyl acetate (100 mL×2), brine (100 mL), andthen dried over Na₂SO₄. The crude product was purified by columnchromatography on silica gel (ethyl acetate in petroleum, 10% v/v) togive Compound A5 (3 g, yield 84%) as a colorless liquid. LC-MS (m/z):472 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) peaks: δ (ppm) 0.000 (s, 3H), 0.024(s, 3H), 0.892 (s, 9H), 4.024-4.116 (m, 1H), 4.402-4.465 (m, 4H), 5.262(s, 2H), 5.421 (m, 1H), 6.066 (d, J=8.0 Hz, 1H), 7.043 (d, J=8.0 Hz,1H), 7.444-7.505 (m, 5H), 7.618-7.639 (m, 2H).

Compound A5 (2 g, 4.2 mmol) was dissolved in THF (30 mL) and thesolution was cooled down to −70° C. under nitrogen atmosphere.L-Selectride (8.5 mL, 1M solution in THF, 8.5 mmol) was added dropwisewhile keeping the temperature at −70° C. After an hour, the reaction wasquenched with saturate NH₄Cl solution and extracted with ethyl acetate(50 mL×2). The extract was dried over Na₂SO₄ to yield a crude productwhich was purified by column chromatography on silica gel (ethyl acetatein petroleum, 10% v/v) to afford Compound A6 (1.4 g, yield 70%) as acolorless oil. LC-MS (m/z): 474 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) peaks: δ(ppm) 0.08 (m, 6H), 0.85 (s, 9H), 3.71 (m, 1H), 3.77 (m, 2H), 4.18 (s,4H), 4.88 (m, 1H), 4.50 (m, 2H), 5.36 (d, J=7.6 Hz, 1H), 6.76 (s, 2H),6.83 (s, 1H), 7.28 (m, 5H).

To a solution of Compound A6 (1.4 g, 3 mmol) in THF (50 mL) was added asolution of TBAF (155 mg, 0.6 mmol) in THF (5 mL) at 0° C., then themixture was stirred at rt overnight. After removal of solvent byevaporation, water (50 mL) was added to the mixture which was thenextracted with ethyl acetate (2×50 mL), washed with brine (1×100 mL),and dried over Na₂SO₄ to obtained Compound A7 (1 g, crude). LC-MS (m/z):342 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) peaks: δ (ppm) 3.620-3.737 (m, 3H),3.772-3.814 (m, 1H), 4.014 (s, 1H), 4.224 (s, 4H), 4.867 (m, 1H), 5.024(s, 2H), 5.607 (d, J=8.8 Hz, 1H), 6.809 (s, 2H), 6.888 (s, 1H), 7.24 (m,5H).

To a solution of Compound A7 (3.6 g, 10 mmol) in THF (50 mL) was addedEt₃N (3 g, 30 mmol), and then the mixture was cooled to −15° C. beforeadding MsCl (0.8 mL) slowly. The mixture was stirred at −15° C. abouthalf an hour. The reaction mixture was taken up with water (30 mL),extracted with ethyl acetate (30 mL×3), dried over anhydrous sodiumsulfate, and evaporated to get Compound A8. To a solution of theresulting mesylate intermediate (A8) in THF (50 mL) was addedpyrrolidine (5.7 g, 80 mmol), K₂CO₃ (11 g, 80 mmol) and NaI (3 g). Themixture was heated at 50° C. overnight. After filtration andevaporation, the crude product was purified by column chromatography onsilica gel (methanol in dichloromethane, 5% v/v) to give Compound A9(2.5 g, yield 61%) as a colorless oil. LC-MS (m/z): 413 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) peaks: δ (ppm) 1.756 (m, 4H), 2.534 (m, 1H), 2.660 (m,4H), 2.877 (m, 1H), 4.019 (m, 1H), 4.236 (s, 4H), 4.924 (d, J=2.8 Hz,1H), 5.043 (s, 2H), 5.079 (m, 1H), 6.7756-6.892 (m, 3H), 7.266-7.361 (m,5H).

To a solution of Compound A9 (2.5 g, 6.1 mmol) in methanol (20 mL) wasadded Pd(OH)₂ (250 mg), and then the mixture was stirred at rt under H₂overnight. The mixture was filtered and the filtrate was evaporated todryness to give Intermediate A (1.7 g). LC-MS (m/z): 279 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) peaks: δ (ppm) 1.70 (m, 4H), 2.53 (m, 6H), 3.05 (m,1H), 4.18 (s, 4H), 4.47 (d, J=3.6 Hz, 1H), 6.75 (m, 3H).

To a solution of 5-fluoro-2-hydroxybenzaldehyde (14.0 g, 0.1 mol) in THF(150 mL) was added dropwise sat. aq. NaOH solution (0.05 N, 300 mL, 15mmol) at 0° C., followed by 30% H₂O₂ solution (40 mL). After stirred for2 h at rt, the second portion of 30% H₂O₂ (40 mL) was added dropwise andstirred for additional 4 h. The reaction mixture was cooled to 0° C. andpH was adjusted to 10-11 using aq. NaOH solution (2 N, 60 mL). Themixture was stirred for 0.5 h before it was quenched with cone. HCl at0° C. to pH 2˜3. The mixture was extracted with DCM (150 mL×3) andwashed with brine (150 mL×1), dried over sodium sulfate, and evaporatedto dryness to yield Compound B1 (12.8 g, yield 100%) as a yellow oil.¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 6.38-6.56(m, 1H), 6.53-6.56 (m, 1H), 6.66-6.70 (m, 1H), 8.83 (s, 1H), 9.30 (s,1H).

A mixture of Compound B1 (12.8 g, 0.1 mol), Cs₂CO₃ (81.5 g, 0.25 mol) inDMF (200 mL) was first stirred for 0.5 h at 40° C. and then1,2-dibromoethane (11.7 mL, 0.135 mol) was added and the mixture wasstirred for 16 h at 80° C. After it was cooled down to rt, the mixturewas filtered and the cake was washed with ethyl acetate (100 mL). Thefiltrate was diluted with water (400 mL) and extracted with ethylacetate (200 mL×3). The combined organic layer was washed with water(200 mL×5) and brine (200 ml×1), dried over sodium sulfate,concentrated, and purified by column chromatography on silica gel (ethylacetate/PE=1/20, v/v) to get Compound B2 (4.3 g, yield 30%) as a yellowoil. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)4.20-4.25 (m, 4H), 6.51-6.56 (m, 1H), 6.58-6.61 (m, 1H), 6.76-6.80 (m,1H).

To a solution of Compound B2 (4.1 g, 26.5 mmol) and NBS (7.1 g, 40 mmol)in ACN (30 mL) was added TFA (302 mg, 2.65 mmol) at rt and the mixturewas kept at rt with stirring overnight. Upon removal of the solvents,the residue was purified by column chromatography on silica gel (ethylacetate/PE=1/25, v/v) to yield Compound B3 (4.9 g, yield 79%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)4.21-4.26 (m, 4H), 6.67-6.69 (d, J=9.2 Hz, 1H), 7.02-7.04 (d, J=6.8 Hz,1H).

To a solution of Compound B3 (700 mg, 53.7 mmol) in THF (10 mL) wasadded n-BuLi (2.5M, 1.24 mL, 3.1 mmol) at −60° C. under N₂. After 30min, a solution of (R)-benzyl4-formyl-2,2-dimethyloxazolidine-3-carboxylate (263 mg, 1 mmol) in THF(3 mL). The mixture was stirred at −60° C. under N₂ for an additional 30min, before it was quenched with saturated aqueous NH₄Cl solution (20mL). The mixture was extracted with ethyl acetate (20 mL×3), washed withbrine (20 mL×1), dried over anhydrous Na₂SO₄, and purified by columnchromatography on silica (ethyl acetate in petroleum, 30% v/v) to yieldCompound B4 (120 mg, yield 29%) as a white foam. LCMS (m/z): 440 [M+1]⁺;¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.41-1.70(m, 6H), 3.63-3.94 (m, 1.5H), 4.09 (m, 0.5H), 4.19 (m, 4H), 4.29-4.41(m, 1H), 4.95-4.98 (m, 1H), 5.09-5.22 (m, 2H), 6.54 (m, 1H), 6.98 (m,1H), 7.35 (m, 5H).

To a solution of Compound B4 (2 g, 4.8 mmol) in THF (20 mL) was added 3N HCl (8 mL) and stirred at 50° C. for 6 h. The mixture was diluted withwater (50 mL), extracted with ethyl acetate (30 mL×3), washed with brine(30 mL×1), dried over anhydrous Na₂SO₄, and concentrated to obtainCompound B5 (1.8 g, yield 100%) as a yellow oil. LCMS (m/z): 400[M+23]⁺.

To a solution of Compound B5 (1.8 g, 4.8 mmol) and Et₃N (1 mL, 7.2 mmol)in THF (40 mL) was added MsCl (1.44 mL) at −50° C. Stirred at thistemperature for 2 h under N₂, the reaction was quenched with sat.aqueous NaHCO₃ solution (50 mL). It was extracted with ethyl acetate (50mL×3), washed with brine (30 mL×1), dried with anhydrous Na₂SO₄,purified with a silica gel column (MeOH in DCM, 3% v/v) to give CompoundB6 (1.2 g, yield 55%) as a colorless oil. LCMS (m/z): 478 [M+23]⁺;¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.94-3.09(m, 3H), 4.13-4.55 (m, 7H), 5.00-5.31 (m, 4H), 6.56-6.60 (m, 1H),6.94-6.98 (m, 1H), 7.27-7.37 (m, 5H).

To a solution of Compound B6 (1.2 g, 2.6 mmol) in THF (40 mL) was addedpyrrolidine (2 mL, 23.7 mmol) and stirred at 50° C. overnight. After themixture was cooled down, the mixture was diluted with water (100 mL),extracted with ethyl acetate (50 mL×3), washed with water (100 mL×3),brine (100 mL×1), dried over anhydrous Na₂SO₄, and purified using silicagel column chromatography (MeOH in DCM, 4% v/v) to obtain Compound B7(0.4 g, 36%) as a white solid. LCMS (m/z): 431 [M+1]⁺.

To a solution of Compound B7 (400 mg, 0.93 mmol) in EtOH (20 mL) andwater (2 mL) was added LiOH.H₂O (120 mg, 2.79 mmol). The mixture wasstirred at reflux for 4 h, followed by addition of water (50 mL). Themixture was extracted with ethyl acetate (30 mL×3), washed with brine(50 mL×1), dried over anhydrous Na₂SO₄, and concentrated to giveIntermediate B (300 mg, yield 100%) as a yellow solid. LCMS (m/z): 297[M+1]⁺.

To a solution of Compound C1 (50 g, 357 mmol) in ACN (400 mL) was addedNBS (60.08 g, 360 mmol) and HC(O)O—NH₄+(2.47 mg, 39 mmol) at rt and thenthe mixture was stirred at rt for 2 h. After removal of the solvent anddiluted with ethyl acetate (200 mL), the mixture was washed with brine,dried over anhydrous Na₂SO₄, and concentrated to give Compound C2 (78 g,yield 100%) as a yellow solid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 7.48-7.23 (m, 2H), 9.87 (s, 1H), 10.89 (s,1H).

To a solution of Compound C2 (40 g, 183 mmol) in THF (260 mL) was addeddropwise aq. NaOH solution (0.05 N, 720 mL, 37 mmol) at 0° C., and then30% H₂O₂ solution (90 mL). The mixture was stirred for 2 h at rt andfollowed by the addition of a second portion of 30% H₂O₂ (90 mL). Afterstirred for 4 h, it was cooled to 0° C. and aq. NaOH solution (2 N, 112mL) was added until pH10˜11 was reached, and then the mixture wasstirred for 0.5 h and quenched with conc. HCl at 0° C. to pH2˜3. It wasextracted with dichloromethane (250 mL×3) and washed with brine (300mL×2), dried over Na₂SO₄, and concentrated to give Compound C3 (37 g,yield 98%) as a yellow oil. LC-MS (m/z): 205 [M−1]⁻.

To a mixture of Compound C3 (30 g, 146 mol), K₂CO₃ (60.3 g, 437 mol) inDMF (450 mL) was added 1,2-dibromoethane 63 mL, 730 mol). The mixturewas stirred at 80° C. for 4 h. After cooled to rt, it was filtered andthe cake was washed with ethyl acetate (100 mL). The filtrate wasdiluted with water (900 mL) and extracted with ethyl acetate (400 mL×3).The organic layer was washed with water (900 mL×5) and brine (900 ml×1),dried, concentrated, and purified by column chromatography on silica gel(ethyl acetate in petroleum, 5% v/v) to afford Compound C4 (20.4 g,yield 60%) as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 4.35 (s, 4H), 6.91 (t, J=8 Hz, 2H), 7.33(s, 1H).

To a solution of Compound C4 (10.5 g, 45 mmol) in THF (300 mL) was addedn-BuLi (2.4 M, 20 mL, 46.5 mmol) at −60° C. under N₂ and it was stirredat under this condition for 0.5 h. It was added a solution of CompoundA4 (6 g, 15 mmol) in THF (10 mL). The mixture was stirred at −60° C.under N₂ for 20 min, quenched with saturated aqueous NH₄Cl solution (200mL), extracted with ethyl acetate (200 mL×3), washed with brine (200mL×1), dried over anhydrous Na₂SO₄, and purified by columnchromatography on silica gel (ethyl acetate in petroleum, 10% v/v) toobtain Compound C5 (4.87 g, yield 66%) as a colorless oil. LC-MS (m/z):490 [M+1]⁺.

To a solution of Compound C5 (4 g, 8.1 mmol) in THF (50 mL) was addedL-Selectride (16.3 mL) at −60° C. under N₂. The mixture was stirredunder the same condition for 1 h before quenched with saturated aqueousNH₄Cl solution (50 mL). It was extracted with ethyl acetate (50 mL×3),washed with brine, dried over anhydrous Na₂SO₄, and purified by columnchromatography on silica gel (ethyl acetate in petroleum, 9% v/v) toyield Compound C6 (4 g, yield 100%) as a colorless oil. LC-MS (m/z): 474[M+1-18]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)3.77-3.83 (m, 2H), 4.28 (t, J=8 Hz, 4H), 4.92-5.05 (m, 2H), 5.11 (m,1H), 5.38-5.57 (m, 1H), 6.67-6.74 (m, 2H), 7.29-7.36 (m, 5H).

To a solution of Compound C6 (4.15 g, 8.4 mmol) in THF (150 mL) wasadded TBAF (1.1 g, 4.2 mmol) at 0° C. and it was stirred at rtovernight. The mixture was added water (100 mL), extracted with ethylacetate (50 mL×3), washed with brine (100 mL×2), dried over anhydrousNa₂SO₄, and concentrated to give Compound C7 (3.18 g, yield 100%) as acolorless oil. LC-MS (m/z): 360 [M+1-18]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 4.14-4.16 (m, 6H), 4.91 (s, 2H), 4.98 (s,1H), 5.47 (d, J=8 Hz, 2H), 6.55-6.63 (m, 2H), 7.17-7.26 (m, 5H).

To a solution of Compound C7 (3.18 g, 8.4 mmol) and Et₃N (3.5 mL, 25.3mmol) in THF (80 mL) was added MsCl (0.71 mL, 9.3 mmol) at −40° C. andthe mixture was stirred at −40° C. for 4 h. It was added water (100 mL),extracted with ethyl acetate (50 mL×3), washed with brine (100 mL×1),dried over anhydrous Na₂SO₄, and purified by column chromatography onsilica gel (ethyl acetate in petroleum, 30% v/v) to give Compound C8(1.35 g, yield 35%) as a colorless oil. LC-MS (m/z): 438 [M+1-18]⁺.

To a solution of Compound C8 (1 g, 3 mmol) in THF (20 mL) was addedpyrrolidine (2.66 mL, 30 mmol). The mixture was stirred at 60° C.overnight. It was added water (20 mL), extracted with ethyl acetate (10mL×3), washed with brine (30 mL×1), dried over anhydrous Na₂SO₄ andconcentrated in vacuum to give Compound C9 (900 mg, crude) as a yellowoil. LC-MS (m/z): 431 [M+1]⁺.

To a solution of Compound C9 (900 mg, 2.1 mmol) in EtOH/water (20 mL,9:1, v/v) was added LiOH.H₂O (264 mg, 6.3 mmol). The mixture wasrefluxed for 36 h and then diluted with water (20 mL). It was extractedwith ethyl acetate (20 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuum to give Intermediate C(800 mg, crude) as a yellow oil. LC-MS (m/z): 297 [M+1]⁺.

To a solution of Compound D1 (80 g, 266 mmol) in CH₃CO₂H (400 ml) wasadded fuming HNO₃ (24 mL) at 10° C. and the mixture was stirred at 32°C. for 1 h. Water (200 mL) was added and the mixture filtered. Thefiltrate was washed with water to remove CH₃CO₂H and was dried to giveCompound D2 (80 g, yield 82%) as a yellow solid. LC-MS (m/z): 244[M−1]⁻.

To a solution of Compound D2 (40 g, 163 mmol) in THF (260 mL) was addeddropwise aq. NaOH solution (0.05 N, 640 mL, 33 mmol) at 0° C. and 30%H₂O₂ solution (80 mL). The mixture was stirred for 2 h at rt. The secondportion of 30% H₂O₂ (80 mL) was added dropwise and the mixture wasstirred for 4 h. After cooling to 0° C., aq. NaOH solution (2 N, 98 mL)was added dropwise until pH10˜11. The mixture was stirred for 0.5 h andquenched with conc. HCl at 0° C. until pH 2˜3. The mixture was extractedwith dichloromethane (250 mL×3) and washed with brine (300 mL×2), driedover Na₂SO₄, and concentrated to give Compound D3 (37 g, yield 98%) as ayellow solid. LC-MS (m/z): 232 [M−1]⁻; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 7.17 (s, 1H), 7.48 (s, 1H), 10.59 (s, 2H).

To a mixture of Compound D3 (32 g, 137 mol) and K₂CO₃ (73 g, 549 mol) inDMF (500 mL) was added 1,2-dibromoethane (147 mL, 343 mol). The mixturewas stirred at 80° C. for 4 h. After cooling to rt, the mixture wasfiltered and the cake was washed with ethyl acetate (100 mL). Thefiltrate was diluted with water (900 mL) and extracted with ethylacetate (400 mL×3). The organic layer was washed with water (900 mL×5)and brine (900 ml×1), dried, concentrated, and purified by columnchromatography on silica gel (ethyl acetate in petroleum, 5% v/v) toyield Compound D4 (30 g, yield 84%) as a colorless oil. ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 4.35 (s, 4H), 6.91 (t, J=8Hz, 2H), 7.33 (s, 1H).

To a solution of Compound D4 (11 g, 42.5 mmol) in EtOH (200 mL) wasadded HCl (7 mL). Fe (7.1 g, 127 mmol) was added over 0.5 h. Then HClwas added to reach pH 3-4. The mixture was stirred at 100° C. for 2 h.After cooling to rt, 10% NaOH aq was added dropwise until pH 10˜11. Themixture was filtered and the cake was washed with THF. The filtrate wascondensed and extracted with ethyl acetate (100 mL×3), washed with brine(200 mL×1), dried over anhydrous Na₂SO₄, concentrated, and purified bycolumn chromatography on silica gel (ethyl acetate in petroleum, 20%v/v) to obtain Compound D5 (9 g, yield 93%) as a white solid. LC-MS(m/z): 230 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 4.23-4.27 (m, 4H), 6.46 (d, J=8 Hz, 2H).

A solution of D5 (3.3 g, 14.7 mmol) in H₂O (15 mL) and concentrated HCl(4 mL, 48 mmol) was cooled to 5° C. A solution of NaNO₂ (1.09 g, 15.8mmol) in H₂O (7 mL) was added dropwise. The brown solution of thediazionium salt was then added dropwise to a solution of CuCl (2.96 g,28.4 mmol) in concentrated HCl (5 mL), maintaining the internaltemperature around 10° C. The mixture was then diluted with H₂O (120 ml)and the solution was stirred for an additional 1 h at rt. The productwas extracted into ethyl acetate (50 mL×3), washed with brine (200mL×1), dried over anhydrous Na₂SO₄, concentrated, and purified by columnchromatography on silica gel (ethyl acetate in petroleum, 20% v/v) toobtain Compound D6 (1.9 g, yield 53%) as a white solid. ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 4.26 (t, J=8 Hz, 2H), 4.34(t, J=8 Hz, 2H), 6.95 (s, 1H), 7.08 (s, 1H).

To a solution of Compound D6 (8.05 g, 32 mmol) in THF (300 mL) was addedn-BuLi (2.4 M, 14 mL, 29.4 mmol) at −60° C. under N₂ and stirred for 0.5h. Then it was added a solution of Compound A6 (4.3 g, 11 mmol) in THF(10 mL). The mixture was stirred at −60° C. under N₂ for 20 min,quenched with saturated aqueous NH₄Cl solution (200 mL), extracted withethyl acetate (200 mL×3), washed with brine (200 mL×1), dried overanhydrous Na₂SO₄, purified by column chromatography on silica gel (ethylacetate in petroleum, 10% v/v) to yield Compound D7 (4.87 g, yield 66%)as a colorless oil. LC-MS (m/z): 506 [M+1]⁺.

To a solution of Compound D7 (4.5 g, 8.8 mmol) in THF (50 mL) was addedL-selectride (17.7 mL) at −60° C. under N₂. After stirred for 1 h, themixture was quenched with saturated aqueous NH₄Cl solution (50 mL),extracted with ethyl acetate (50 mL×3), washed with brine, dried overanhydrous Na₂SO₄, and purified by column chromatography on silica gel(ethyl acetate in petroleum, 20% v/v) to give Compound D8 (3.8 g, yield85%) as a white solid. LC-MS (m/z): 490 [M+1-18]⁺; ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 0.90 (s, 9H), 3.77-3.85 (m,2H), 4.25 (s, 2H), 4.34 (s, 2H), 4.90 (s, 1H), 5.01-5.12 (m, 2H), 5.40(d, J=8 Hz, 1H), 6.80 (s, 1H), 6.97 (s, 1H), 7.32-7.36 (m, 5H).

To a solution of Compound D8 (3.8 g, 7.5 mmol) in THF (150 mL) was addedTBAF (1 g, 3.8 mmol) at 0° C. and it was stirred at rt overnight. Themixture was added water (100 mL), extracted with ethyl acetate (50mL×3), washed with brine (100 mL×2), dried over anhydrous Na₂SO₄, andconcentrated to yield D9 (2.81 g, yield 100%) as a colorless oil. LC-MS(m/z): 376 [M+1-18]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 3.72-3.80 (m, 2H), 4.23 (s, 2H), 4.31 (s, 2H), 4.69-4.86(m, 1H), 5.02-5.15 (m, 2H), 5.51 (d, J=8 Hz, 1H), 6.75-6.96 (m, 2H),7.29-7.36 (m, 5H).

To a solution of Compound D9 (1.4 g, 3.6 mmol) and TEA (1.5 mL, 10.8mmol) in THF (30 mL) was added MsCl (0.31 mL, 3.9 mmol) at −40° C. Afterstirring at −0° C. for 4 h, water (50 mL) was added and the product wasextracted into ethyl acetate (50 mL×3) which was washed with brine (100mL×1) and dried over anhydrous Na₂SO₄. The product was purified bycolumn chromatography on silica gel (ethyl acetate in petroleum, 50%v/v) to give Compound D10 (756 mg, yield 45%) as a white solid. LC-MS(m/z): 454 [M+1-18]⁺.

To a solution of Compound D10 (756 mg, 1.6 mmol) in THF (20 mL) wasadded pyrrolidine (1.4 mL, 16 mmol). The mixture was stirred at 60° C.overnight. It was added water (20 mL), extracted with ethyl acetate (10mL×3), washed with brine (30 mL×1), dried over anhydrous Na₂SO₄, andconcentrated in vacuum to give crude product Compound D11 (715 mg,crude) as a white solid. LC-MS (m/z): 447 [M+1]⁺.

To a solution of Compound D11 (714 mg, 1.6 mmol) in EtOH/water (24 mL,2:1, v/v) was added LiOH.H₂O (672 mg, 16 mmol). The mixture was refluxedfor 24 h before added water (20 mL). It was extracted with ethyl acetate(20 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuum to give crude product Intermediate D (620 mg,crude) as a yellow oil. LC-MS (m/z): 313 [M+1]⁺.

A suspension of Compound A8 (1.00 g, 2.29 mmol),tert-butyl-8-azabicyclo[3.2.1]octan-3-ylcarbamate (1.96 g, 6.86 mmol)and K₂CO₃ (1.58 g, 11.45 mmol) in ACN (30 mL) was stirred at 60° C.overnight. The mixture was diluted with ethyl acetate (150 mL) andevaporated to give Compound E1 (1.20 g, yield 92%) as a colorless oil.LCMS (m/z): 568 [M+1]⁺.

A mixture of Compound E1 (1.20 g, 2.12 mmol) and NaOH (423 mg, 10.58mmol) in H₂O/EtOH (10/50 mL) was stirred at 80° C. overnight. Themixture was diluted with ethyl acetate (150 mL), washed with water andbrine, and purified by prep-HPLC to yield Compound E2 (980 mg, yield100%) as a colorless oil. LCMS (m/z): 433 [M+1]⁺.

To a solution of Compound E2 (980 mg, 2.26 mmol) and imidazole (461 mg,6.78 mmol) in THF (10 mL) was added TBDMSCl (678 mg, 4.53 mmol) at rt.The mixture was stirred at rt for 2 h. It was diluted with ethyl acetate(150 mL), washed with water and brine, dried with anhydrous Na₂SO₄, andevaporated to afford Intermediate E (1.10 g, yield 89%) as a colorlessoil, which was used for next step directly. LCMS (m/z): 548 [M+1]⁺.

Example 1

To a stirred solution of Compound 1A (2.75 g, 17 mmol) in DCM (40 mL)was added THF-borane (1 M, 20 mL, 20 mmol) at −78° C. The resultingmixture was allowed to warm up to rt over 1 h. To the mixture was addedMeOH (8 mL) and it was heated to reflux for 2 h. Diluted with aq. NaHCO₃(20 mL), the mixture was poured into crash ice slowly with stirring. Themixture was then extracted with EtOAc (20 mL×3). The combined organiclayers were dried over Na₂SO₄ and concentrated to give the crude productwhich was purified by column chromatography on silica gel (ethyl acetatein petroleum ether, from 1% to 25% v/v) to yield compound 1B (2.4 g,yield 96%) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.79-2.75 (m, 3H), 3.01-3.08 (m, 2H),3.61-3.64 (m, 2H), 7.10-7.23 (m, 4H).

A solution of Compound 1B (200 mg, 1.4 mmol) and Dess-Martin reagent(688 mg, 1.6 mmol) in dichloromethane (20 mL) was stirred at rt for 4 h.The resulting solution was poured into a saturated solution of sodiumhydrogen carbonate (20 mL) in which beforehand sodium thiosulfatepentahydrate had been dissolved. After 15 min of vigorous stirring, theorganic phase was collected and the aqueous phase was extracted withdiethyl ether (10 mL×3). The combined organic layers were dried andevaporated to give a crude product which was purified by columnchromatography on silica gel (ethyl acetate in petroleum ether, from 1%to 4% v/v) to afford Compound 1C (190 mg, yield 96%) as a yellow oil.¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 3.05-3.23(m, 5H), 7.06-7.15 (m, 4H), 9.67 (s, 1H).

Compound 1C (292 mg, 2 mmol) was added to a solution of sodiummetabisulfite (196 mg, 4 mmol) in water (3 mL). The mixture wasvigorously stirred for 2 h at rt and after the addition of sodiumcyanide (380 mg, 2 mmol), and then stirred for 1 h. The mixture wasextracted with diethyl ether (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, and concentrated to give acrude product 1D (316 mg, yield 91%) as a yellow oil. ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 2.89-3.01 (m, 3H), 3.14-3.24(m, 2H), 4.41-4.43 (d, J=8 Hz, 1H), 7.16-7.26 (m, 4H).

A solution of Compound 1D (300 mg, 1.7 mmol) in HCl/MeOH (3 M, 2 mL) washeated to reflux for 18 h. The mixture was concentrated by evaporationand purified by column chromatography on silica gel to give Compound 1E(116 mg, yield 32%). ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks:δ (ppm) 2.85-3.01 (m, 6H), 3.75 (s, 3H), 4.28 (s, 1H), 7.11-7.19 (m,4H).

A solution of Compound 1E (550 mg, 2.70 mmol) and Dess-Martin reagents(1.3 g, 3.2 mmol) in dichloromethane (20 mL) was stirred at rt for 4 h.The suspension was diluted with diethyl ether (60 mL) before beingslowly poured into a saturated solution of sodium hydrogen carbonate (20mL) in which contained a pre-dissolved sodium thiosulfate pentahydrate(1.6 g, 6.4 mmol). After 15 min of vigorous stirring, the organic phasewas collected and the aqueous phase was extracted with diethyl ether (10mL×3). The combined organic layers were dried and evaporated to give acrude product 1F (500 mg, yield 92%) as a yellow oil. ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 3.24-3.26 (d, J=4 Hz, 4H),3.89-3.91 (m, 3H), 4.01-4.05 (m, 1H), 7.14-7.20 (m, 4H).

To a stirred solution of Compound 1F (200 mg, 1 mmol) in DCM (4 mL) wasadded DAST (0.8 mL, 6 mmol) at 0° C. The resulting mixture was stirredat rt for 24 h. The mixture was poured into crash ice slowly withstirring. The mixture was stirred for 30 min, and then extracted withDCM (10 mL×3). The combined organic layers were washed with brine (20mL), dried over Na₂SO₄, and concentrated to give a crude product. Thecrude product was purified by prep-TLC (petroleum ether as the eluent)to give Compound 1G (80 mg, yield 36%). ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.98-3.19 (m, 5H), 3.74 (s, 3H), 7.07-7.17(m, 4H).

To a stirred solution of Compound 1G (140 mg, 0.6 mmol) in EtOH (2 mL)and H₂O (2 mL) was added LiOH.H₂O (50 mg, 1.2 mmol) in ice bath. Theresulting mixture was stirred at rt for 2 h and followed byacidification to pH 2 with 2 M HCl. The mixture was extracted with EtOAc(20 mL×2). The combined organic layers were dried over Na₂SO₄, andconcentrated to give Compound 1H (130 mg, yield 100%) as yellow oil.LC-MS (m/z): 211 [M-1]⁻; H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 3.09-3.12 (m, 5H), 7.13-7.18 (m, 4H).

To a stirred mixture of Compound 1H (31.8 mg, 0.15 mmol) andIntermediate A (62.55 mg, 0.23 mmol) in DMF (3 mL) was added HOBt (30mg, 0.25 mmol) and EDCI (43.2 mg, 0.23 mmol). The resulting mixture wasstirred at rt overnight. The mixture was diluted with water (15 mL), andextracted with EtOAc (15 mL×3). The combined organic layers were washedwith brine (15 mL), dried over Na₂SO₄, and concentrated to give a crudeproduct. The crude product was purified by prep-HPLC to affordtrifluoroacetic acid salt of Compound 1 (11.1 mg, yield 15.5%) as awhite solid. LC-MS (m/z): 473 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.62 (s, 4H), 2.16 (s, 4H), 2.58-2.64 (m,2H), 2.85-3.09 (m, 4H), 3.52-3.57 (m, 1H), 3.52-3.57 (m, 1H), 4.11-4.21(m, 4H), 4.39-4.41 (m, 1H), 5.16 (s, 1H), 6.80-6.90 (m, 3H), 7.13-7.15(t, J=4 Hz, 4H), 7.37-7.39 (d, J=8 Hz, 1H).

Example 2

To a stirred suspension of AlCl₃ (26.7 g, 200 mmol) in DCM (100 mL) wasadded dropwise ethyl 2-chloro-2-oxoacetate (27.3 g, 200 mL) at 0° C.After stirred at 0° C. for 30 min, 2, 3-dihydrobenzo[b][1,4]dioxine(13.6 g, 100 mmol) was added dropwise at 0° C. to the mixture. Theresulting mixture was stirred at rt for 3 h, poured into ice water (300mL), and then extracted with DCM (150 mL×3). The combined organic layerswere washed with aq. NaHCO₃ (200 mL), brine (200 mL), dried over Na₂SO₄,and concentrated to give a crude product. The crude product was purifiedby column chromatography on silica gel (ethyl acetate in petroleumether, from 5% to 10% v/v) to yield Compound 2A (18 g, yield 76%) as ayellow solid. LC-MS (m/z): 162 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.40-1.43 (t, J=7.2 Hz, 3H), 4.28-4.33 (m,2H), 4.34-4.36 (m, 2H), 4.40-4.45 (m, 2H), 6.94-6.96 (dd, J=7.6, 1.6 Hz,1H), 7.54-7.56 (m, 2H).

To a stirred solution of Compound 2A (4.72 g, 20 mmol) in DCM (50 mL)was added DAST (16.1 g, 100 mmol) at 0° C. The resulting mixture wasstirred at rt for 24 h and poured into crash ice slowly with stirring.The mixture was stirred for 30 min, and then extracted with DCM (40mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, and concentrated to give crude product. The crude productwas purified by column chromatography on silica gel (ethyl acetate inpetroleum ether, from 0% to 3% v/v) to afford Compound 2B (4.28 g, yield83%) as a yellow oil. LC-MS (m/z): 259 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 1.29-1.33 (t, J=7.2 Hz, 3H),4.26-4.32 (m, 6H), 6.90-6.92 (d, J=8.0 Hz, 1H), 7.07-7.12 (dd, J=7.6,2.4 Hz, 1H), 7.12-7.13 (d, J=2.0 Hz, 1H).

To a stirred solution of Compound 2B (4.28 g, 16.59 mmol) in THF (20 mL)and H₂O (20 mL) was added LiOH.H₂O (1.393 g, 33.18 mmol) in an ice bath.The resulting mixture was stirred at rt for 16 h. THF was removed underreduced pressure. The residue was diluted with water (20 mL), acidifiedto pH 2 with 2 M HCl, and then extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated to giveCompound 2C (3.8 g, yield 98%) as light yellow solid. LC-MS (m/z): 211[M−19]⁺; H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)4.28-4.30 (t, J=4.4 Hz, 4H), 6.98-7.04 (m, 3H).

To a stirred mixture of Compound 2C (23 mg, 0.1 mmol) and Intermediate A(41.7 mg, 0.15 mmol) in DMF (1 mL) was added HOBt (20 mg, 0.15 mmol) andEDCI (30 mg, 0.15 mmol). The resulting mixture was stirred at rtovernight. The mixture was diluted with water (10 mL) and extracted withEtOAc (10 mL×3). The combined organic layers were washed with brine (10mL), dried over Na₂SO₄, and concentrated to give crude product. Thecrude product was purified by prep-HPLC to give trifluoroacetic acidsalt of Compound 2 (18.9 mg, yield 39%) as a white solid. LC-MS (m/z):491 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)2.07 (s, 3H), 2.86 (s, 1H), 3.00 (s, 1H), 3.46 (s, 2H), 3.76 (s, 2H),4.20-4.25 (m, 8H), 4.37 (s, 1H), 5.05 (s, 1H), 6.72-6.81 (m, 4H), 6.91(s, 1H), 7.65 (s, 1H), 11.67 (s, 1H).

Example 3

To a solution of 5-chlorobenzo[b]thiophene (2.00 g, 11.83 mmol) in THF(50 mL) was added dropwise n-BuLi in THF (5.20 mL, 13.01 mmol) at −78°C. Then it was stirred at −50° C. for 1 h. Diethyl oxalate (4.32 g,29.58 mmol) was added to the mixture quickly at −78° C. The mixture wasstirred at −50° C. for 1 h. It was quenched with acetic acid, dilutedwith ethyl acetate (200 mL), washed with water and brine, dried withanhydrous Na₂SO₄, and evaporated to give a residue which was washed withpetroleum ether to obtain Compound 3A (2.60 g, yield 82%) as a lightyellow solid. LCMS: 269 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.46 (t, J=7.6 Hz, 3H), 4.45-4.51 (m, 2H),7.48 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 8.37 (s,1H).

To a solution of Compound 3A (600 mg, 2.25 mmol) in DCM (120 mL) wasadded dropwise DAST (1.5 mL, 11.19 mmol) at rt. The mixture was stirredat rt overnight. It was then quenched with ice, diluted with ethylacetate (150 mL), washed with water and brine, dried with anhydrousNa₂SO₄, and evaporated to yield Compound 3B (420 mg, yield 64%) as ayellow oil. LCMS: 291 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.37 (t, J=7.2 Hz, 3H), 4.35-4.41 (m, 2H),7.38 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.77-7.82 (m, 2H).

A solution of Compound 3B (420 mg, 1.45 mmol) and LiOH.H₂O (122 mg, 2.90mmol) in THF/MeOH/H₂O (10/10/5 mL) was stirred at rt for 2 h. Themixture was adjusted to pH 2 with conc. HCl, diluted with ethyl acetate(150 mL), washed with water and brine, dried with anhydrous Na₂SO₄, andevaporated to give Compound 3C (400 mg, yield 100%) as a white solid.LCMS: 261 [M−1]⁻.

A mixture of Intermediate A (80 mg, 0.29 mmol), Compound 3C (94 mg, 0.34mmol), EDCI (84 mg, 0.44 mmol), HOBt (59 mg, 0.44 mmol) and DIPEA (0.2mL) in DCM (5 mL) was stirred at rt overnight. Then it was diluted withethyl acetate (150 mL) washed with water and brine, purified byprep-HPLC to afford Compound 3 (50 mg, yield 33%) as a white solid.LCMS: 523 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.14 (br s, 4H), 2.59 (br s, 4H), 2.89-3.03 (m, 2H), 3.45-3.51 (m,2H), 3.82 (br s, 2H), 4.00-4.16 (m, 4H), 4.44 (br s, 1H), 5.15 (s, 1H),6.72-6.82 (m, 3H), 7.10 (s, 1H), 3.37 (d, J=10.4 Hz, 1H), 7.70-7.78 (m,2H), 11.95 (s, 1H).

Example 4

To a solution of 4-bromo-2-fluorophenol (15 g, 78.5 mmol) in DMF (200mL) was added K₂CO₃ (32.25 g, 235.6 mmol), CH₃I (12.3 mL, 96.3 mmol).The mixture was stirred at rt overnight. Water (500 mL) was added to themixture and the mixture was extracted with ethyl acetate (200 mL×3),dried over anhydrous Na₂SO₄, and purified by column chromatography onsilica gel (petroleum 100%) to obtain Compound 4A (11.3 g, 70%) as acolorless oil. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 3.86 (s, 3H), 6.83 (t, J=8.8 Hz, 1H), 7.20 (m, 2H).

To a solution of Compound 4A (11 g, 53.7 mmol) in THF (250 mL) was addedn-BuLi (2.5M, 22.2 mL, 55.5 mmol) at −60° C. under N₂. The mixture wasstirred at −0° C. under N₂ for 0.5 h. Then it was added a solution ofIntermediate A4 (7.1 g, 17.9 mmol) in THF (50 mL). The mixture wasstirred at −60° C. under N₂ for another 5 min before quenched withsaturated aqueous NH₄Cl solution (200 mL). The mixture was extractedwith ethyl acetate (200 mL×3), washed with brine (200 mL×1), dried overanhydrous Na₂SO₄, and purified by column chromatography on silica (ethylacetate in petroleum, 9% v/v) to yield Compound 4B (7.1 g, 86%) as acolorless oil. LCMS: 462 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) −0.14 (s, 3H), −0.12 (s, 3H), 0.75 (s,9H), 3.89 (m, 1H), 3.96 (m, 4H), 5.13 (s, 2H), 5.29 (m, 1H), 5.89 (m,1H), 7.01 (m, 1H), 7.35 (m, 5H), 7.73 (m, 2H).

To a solution of Compound 4B (7.1 g, 15.4 mmol) in THF (100 mL) wasadded L-Selectride (31 mL) at −60° C. under N₂ and stirred at −60° C.under N₂ for 1 h. The mixture was quenched with saturated aqueous NH₄Clsolution (100 mL) and extracted with ethyl acetate (100 mL×3), washedwith brine, dried over anhydrous Na₂SO₄, and then purified by columnchromatography on silica gel (ethyl acetate in petroleum, 9% v/v) togive Compound 4C (6.7 g, 94%) as a colorless oil. LCMS: 446 [M+1-18]⁺;¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 0.03 (m,6H), 0.90 (d, 9H), 3.68 (m, 1H), 3.88 (m, 5H), 4.89 (m, 1H), 5.04 (m,2H), 5.39 (m, 1H), 6.88 (m, 1H), 7.03 (m, 1H), 7.12 (m, 1H), 7.30 (m,5H).

To a solution of Compound 4C (6.7 g, 13.6 mmol) in THF (250 mL) wasadded TBAF (1.8 g, 6.8 mmol) at 0° C. and stirred at rt overnight. Themixture was added water (200 mL), extracted with ethyl acetate (100mL×3), washed with brine (200 mL×1), dried over anhydrous Na₂SO₄,concentrated to obtain Compound 4D (5 g, 98%) as a yellow oil. LCMS: 332[M+1-18]⁺.

To a solution of Compound 4D (5 g, 14.3 mmol) and TEA (6 mL, 42.9 mmol)in THF (80 mL) was added MsCl (1.2 mL) at −60° C. and stirred at −60° C.for 2 h. The mixture was added pyrrolidine (12 mL, 143 mmol) and stirredat 50° C. overnight. After the mixture was cooled down, water (200 mL)was added. The mixture was extracted with ethyl acetate (100 mL×3). Thecombined organic layers were washed with brine (200 mL×1), and driedover anhydrous Na₂SO₄. The crude product was purified by prep-HPLC toobtain Compound 4E (1.9 g, 33%) as a colorless oil. LCMS: 403 [M+1]⁺;¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.78 (m,4H), 2.64 (m, 6H), 3.88 (m, 4H), 5.03 (m, 4H), 6.89 (m, 1H), 6.70 (m,1H), 7.11 (m, 1H), 7.28 (m, 5H).

To a solution of Compound 4E (1.9 g, 4.7 mmol) in MeOH (30 mL) was addedPd(OH)₂ (660 mg, 4.7 mmol). The mixture was stirred at rt overnightunder H₂. The mixture was filtered and the filtrate was concentrated toobtain Compound 4F (1.2 g, 95%) as a colorless oil. LCMS: 269 [M+1]⁺.

To a mixture of Compound 4F (194 mg, 0.74 mmol) in DCM (10 mL) was addedEDCI (213 mg, 1.1 mmol), HOBt (150 mg, 1.11 mmol) and Compound 3C (200mg, 0.74 mmol) and stirred at rt for overnight. Then it was added water(50 mL), extracted with DCM (20 mL×3), dried over anhydrous Na₂SO₄,purified by prep-HPLC to give 4 (50 mg, 14%) as a white solid. LCMS: 514[M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm)1.88 (m, 2H), 2.02 (m, 2H), 3.12 (m, 2H), 3.49 (s, 3H), 3.56 (m, 4H),4.28 (m, 1H), 4.48 (d, J=9.2 Hz, 1H), 6.06 (br, 1H), 6.71 (t, J=8.8 Hz,1H), 6.93 (d, J=8 Hz, 1H), 7.05 (dd, 1H), 7.20 (s, 1H), 7.52 (dd, 1H),7.95 (d, J=2.4 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 9.23 (m, 1H), 9.78 (br,1H).

Example 5

To a mixture of Compound 4F (157 mg, 0.74 mmol) in DCM (10 mL) was addedEDCI (213 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and Compound 1H (200mg, 0.74 mmol) and stirred at rt overnight. Water (50 mL) was added tothe mixture, which was then extracted with DCM (20 mL×3). The combinedorganic phases were dried over anhydrous Na₂SO₄ and evaporated to removesolvents. The residues were purified by prep-HPLC to yield 5 (30 mg,yield 9%) as a white solid. LCMS: 463 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz)major characteristic peaks: δ (ppm) 1.88 (m, 2H), 2.03 (m, 2H), 3.10 (m,2H), 3.54 (m, 5H), 3.76 (s, 3H), 4.31 (m, 1H), 4.50 (d, J=7.2 Hz, 1H),6.09 (br, 1H), 7.13 (m, 7H), 8.86 (d, J=8.8 Hz, 1H), 9.51 (br, 1H).

Example 6

To a solution of 5-chlorobenzo[d]thiazole (500 mg, 2.95 mmol) in THF (20mL) was added n-BuLi (1.42 ml, 3.54 mmol) at −78° C. under theprotection of nitrogen. The mixture was stirred at −78° C. for 1 h, andthen diethyl oxalate (1.08 g, 7.37 mmol) was added to the mixture andstirred for additional one hour at −78° C. The reaction was quenchedwith sat. aqueous NH₄Cl. The organic phase was separated and washed withbrine, dried over anhydrous Na₂SO₄, and purified with columnchromatography on silica gel (ethyl acetate in petroleum 20% v/v) togive Compound 6A (200 mg, yield 25%) as a yellow solid. LCMS (m/z): 288[M+18]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)1.46 (t, J=7.2 Hz, 3H), 4.54 (q, J=7.2 Hz, 2H), 7.57 (dd, J=2.0, 8.8 Hz,1H), 7.95 (d, J=8.8 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H).

To a solution of Compound 6A (170 mg, 0.63 mmol) in DCM (10 mL) wasadded DAST (305 mg, 1.89 mmol) at 0° C. under N₂ and stirred at 15° C.overnight. The reaction mixture was poured into 100 mL of ice-water andextracted with DCM (50 mL×3). The combined organic phase was washed withbrine, and dried over anhydrous Na₂SO₄, and purified by columnchromatography on silica gel (ethyl acetate in petroleum, 9% v/v) toyield Compound 6B (105 mg, yield 52%) as a yellow oil. LCMS (m/z): 292[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.27(t, J=7.2 Hz, 3H), 4.43 (q, J=7.2 Hz, 2H), 7.72 (dd, J=2.0, 8.8 Hz, 1H),8.36 (m, 2H).

To a solution of Compound 6B (105 mg, 0.36 mmol) in THF/MeOH/water (6mL, 1:1:1, v/v/) was added LiOH.H₂O (15 mg). The mixture was stirred at25° C. for 2 h. After removal of the solvents and adjust pH to 7 with 1N HCl, the mixture was diluted with ethyl acetate (100 mL), washed withwater, brine, and dried over anhydrous Na₂SO₄. The crude product wasused for next step without further purification. Compound 6C (95 mg,yield 99%) was obtained as a yellow oil. LCMS (m/z): 264 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 7.51 (dd, J=1.6,8.8 Hz, 1H), 7.90 (d, J=8.84 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H).

To a mixture of Compound 6C (95 mg, 0.36 mmol) in DCM (10 mL) was addedEDCI (104 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and Intermediate A(100 mg, 0.36 mmol) and stirred at 25° C. overnight. Diluted with water(5 mL), the mixture was extracted with DCM (20 mL×3). The organic phasewas dried over anhydrous Na₂SO₄ and purified with prep-HPLC to affordCompound 6 (10 mg, yield 6%) as a colorless oil. LCMS (m/z): 524 [M+1]⁺;¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.91 (m,4H), 2.75 (m, 2H), 2.93-3.01 (m, 6H), 3.23 (m, 2H), 4.24 (s, 4H), 4.63(d, J=9.6 Hz, 1H), 6.80 (m, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.8Hz, 1H), 7.93 (d, J=2.0 Hz, 1H).

Example 7

To a solution of 5,6-dichloroisobenzofuran-1,3-dione (12.00 g, 55.30mmol) in THF (300 mL) was added LiAlH₄ (3.15 g, 82.95 mmol) carefully at0° C. The mixture was stirred at rt overnight. It was then quenched withwater (13 mL), 15% aqueous NaOH (3.2 mL). After filtration, the filtratewas evaporated to dryness to yield Compound 7A (11.20 g, yield 98%) as awhite solid. LCMS: 207 [M+1]⁺, ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 4.47 (d, J=5.6 Hz, 4H), 5.34 (t, J=5.6 Hz,2H), 7.57 (s, 2H).

A suspension of Compound 7A (4.80 g, 23.2 mmol) in conc. HBr (100 mL)was stirred at 90° C. overnight. The mixture was diluted with ethylacetate (100 mL) and petroleum ether (100 mL), washed with water andbrine, concentrated, and then purified by silica chromatography onsilica gel (ethyl acetate in petroleum ether, 8% v/v) to give Compound7B (5.20 g, yield 68%) as a light yellow solid. LCMS: 333 [M+1]⁺, ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 4.55 (s, 4H), 7.47(s, 2H).

To a solution of Compound 7B (5.88 g, 36.8 mmol) in THF (300 mL) wasadded NaH (882 mg, 36.8 mmol). The mixture was stirred at rt for 10 min.Then diethyl malonate (12.20 g, 36.75 mmol) was added to the mixture.After stirring for 20 min, an additional portion of NaH (882 mg, 36.8mmol) was added. After stirring at rt overnight, the mixture wasevaporated to dryness to give Compound 7C (12.6 g, yield 100%) as awhite solid. LCMS: 331 [M+1]⁺.

A mixture of Compound 7C (12.6 g, 38.2 mmol) and LiOH.H₂O (5.80 g, 0.15mol) in THF/MeOH/H₂O (100/100/50 mL) was stirred at rt overnight. Themixture was condensed by removal of solvents and adjusted to pH 1 withconc. HCl. The precipitate was filtered to obtain Compound 7D (11.2 g,yield 100%) as a white solid. LCMS: 273 [M−1]⁻, ¹H-NMR (DMSO-d₆, 400MHz) major characteristic peaks: δ (ppm) 3.47 (s, 4H), 7.57 (s, 2H),13.16 (s, 2H).

A mixture of Compound 7D (4.80 g, 17.5 mmol) and NaCl (4.80 g) in DMSO(100 mL) was stirred at 130° C. for 5 h. Diluted with ethyl acetate (200mL), the mixture was washed with water and brine, dried with anhydrousNa₂SO₄, and evaporated to dryness to give Compound 7E (3.40 g, yield84%) as a white solid. LCMS: 229 [M−1]⁻, ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.12-3.23 (m, 4H), 3.34-3.42 (m, 1H), 7.55(s, 2H), 12.45 (s, 1H).

To a solution of Compound 7E (3.40 g, 1.47 mmol) in THF (100 mL) wasadded LiAlH₄ (554 mg, 1.47 mmol). The mixture was stirred at rtovernight. After being quenched with water (2.4 mL) and aqueous NaOH(15%, 0.56 mL), the precipitate was filtered off and the filtrate wasevaporated to give Compound 7F (2.80 g, yield 88%) as a white solid.LCMS: 217 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks:δ (ppm) 2.50-2.60 (m, 1H), 2.89-2.95 (m, 2H), 3.32 (s, 4H), 4.65-4.68(m, 1H), 7.44 (s, 2H).

To a solution of Compound 7F (2.80 g, 12.96 mmol) in DCM (100 mL) wasadded DMP (6.60 g, 15.6 mmol). The mixture was stirred at rt for 2 h.The solids were filtered off and the filtrate was diluted with ethylacetate (200 mL), washed with water and brine, and purified by silicagel chromatography (ethyl acetate in PE, 15% v/v) to give Compound 7G(2.10 g, yield 76%) as a light yellow solid. LCMS: 215 [M+1]⁺; ¹H-NMR(DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 3.06-3.12 (m,2H), 3.19-3.24 (m, 2H), 3.37-3.44 (m, 1H), 7.51 (s, 2H), 9.68 (s, 1H).

A suspension of Compound 7G (2.70 g, 12.6 mmol) and Na₂O₅S₂ (1.24 g,25.2 mmol) in EtOH/H₂O (20/20 mL) was stirred at rt for 2 h before NaCN(1.24 g, 25.24 mmol) was added. The mixture was stirred at rt overnight.It was diluted with ethyl acetate (200 mL), washed with water and brine,purified by silica gel chromatography (ethyl acetate in petroleum ether,30% v/v) to yield Compound 7H (2.10 g, yield 69%) as a white solid.LCMS: 242 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks:δ (ppm) 2.79-2.87 (m, 3H), 3.01-3.08 (m, 2H), 4.57 (t, J=6.8 Hz, 1H),6.60 (d, J=6.4 Hz, 1H), 7.50 (s, 2H).

A solution of Compound 7H (2.10 g, 8.71 mmol) in MeOH (100 mL) wasstirred at rt overnight in the presence of HCl gas. After the additionof water (20 mL), the mixture was stirred at rt for 2 h and then dilutedwith ethyl acetate (200 mL), washed with water and brine, dried withanhydrous Na₂SO₄. Removal of solvents by evaporation gave Compound 71(1.80 g, yield 75%) as a white solid. LCMS: 275 [M+1]⁺; ¹H-NMR (DMSO-d₆,400 MHz) major characteristic peaks: δ (ppm) 2.76-2.92 (m, 5H), 3.63 (s,3H), 4.08 (t, J=5.6 Hz, 1H), 5.65 (d, J=6.0 Hz, 1H), 7.44 (s, 2H).

To a solution of Compound 71 (1.00 g, 3.65 mmol) in DCM (30 mL) wasadded DMP (1.55 g, 3.65 mmol). The mixture was stirred at rt for 2 h. Itwas then diluted with ethyl acetate (200 mL), washed with water andbrine, and purified by silica gel chromatography (ethyl acetate inpetroleum ether, 25% v/v) to afford Compound 7J (880 mg, yield 87%) as awhite solid. LCMS: 273 [M+1]⁺.

To a solution of Compound 7J (272 mg, 1.00 mmol) in DCM (10 mL) wasadded DAST (0.66 mL, 5.00 mmol). The mixture was stirred at 25° C.overnight. It was then diluted with ethyl acetate (150 mL), washed withwater and brine, and purified by silica gel chromatography (ethylacetate in PE, 10% v/v) to yield Compound 7K (210 mg, yield 71%) as awhite solid. LCMS: 295 [M+1]⁺.

A mixture of Compound 7K (120 mg, 0.41 mmol) and LiOH.H₂O (52 mg, 1.23mmol) in THF/MeOH/H₂O (5/5/2 mL) was stirred at rt for 2 h. Afterremoval of solvents, the residues were purified by prep-HPLC to giveCompound 7L (90 mg, yield 78%) as a white solid. LCMS: 279 [M−1]⁻.

A mixture of Intermediate A (100 mg, 0.36 mmol), Compound 7L (100 mg,0.36 mmol), EDCI (103 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and Et₃N(0.2 mL) in DCM (5 mL) was stirred at 25° C. overnight. It was dilutedwith ethyl acetate (150 mL), washed with water and brine, and purifiedby prep-HPLC to afford 7 (50 mg, yield 37%) as a white solid. LCMS: 541[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.14(br s, 4H), 2.52-2.59 (m, 2H), 2.65-2.87 (m, 3H), 2.93-3.11 (m, 3H),3.38-3.50 (m, 2H), 3.82 (br s, 2H), 4.14-4.25 (m, 4H), 4.42 (br s, 1H),5.12 (s, 1H), 6.80-6.88 (m, 3H), 7.21 (s, 2H), 7.45 (br s, 1H), 11.99(s, 1H).

Example 8

Acetyl chloride (10 g, 130 mmol) was added to methanol (100 mL) at 0° C.in an ice-water bath under N₂. The mixture was stirred for 5 min beforeCompound A2 (10 g, 42 mmol) was added. The mixture was heated to refluxand stirred for 2 h. Removal of the solvent by evaporation gave Compound8A (9 g, yield 85%) as a white solid, which was used for the next stepwithout further purification.

To a solution of Compound 8A (10 g, 40 mmol) in acetone (100 mL) wasadded 2,2-dimethoxypropane (37 g, 0.36 mol) and BF₃.Et₂O (2 mL). Theresulting orange solution was stirred at rt for 3 h. The mixture wastreated with TEA (4 mL) and then evaporated to dryness. The resultedresidue was partitioned between ethyl acetate (50 mL) and water (50 mL).The organic layer was washed with brine, and then evaporated to give acrude product, which was purified by silica gel column chromatography(ethyl acetate in petroleum ether, 10% v/v) to yield Compound 8B (7.5 g,yield 80%) as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.49-1.57 (d, 3H), 1.64-1.71 (d, 3H),3.64, 3.77 (s, 3H), 4.08-4.19 (m, 2H), 4.47-4.57 (m, 1H), 5.03-5.20 (m,2H), 7.28-7.37 (m, 5H).

To a solution of Compound 8B (6 g, 20 mmol) in toluene (50 mL) at −78°C. was added 1.0 M DIBAL (30 mL). The mixture was stirred at thistemperature for 2 h, quenched with menthol (6 mL), diluted with 1 N aqHCl (25 mL), extracted with ethyl acetate (50 mL×2), washed with brine(100 mL×2), and evaporated to remove the volatiles. The crude productwas purified by silica gel column chromatography (ethyl acetate inpetroleum ether, 10% v/v) to give Compound 8C (2.7 g, yield 51%) as acolorless oil. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.51-1.58 (d, 3H), 1.60-1.68 (d, 3H), 4.08-4.16 (m, 2H), 4.31-4.36(m, 1H), 5.10 (m, 2H), 7.28-7.37 (m, 5H), 9.56-9.63 (s, 1H).

To a solution of 2-bromo-1-fluoro-4-methoxybenzene (3.5 g, 34 mmol) inTHF (60 mL) was added n-BuLi (9.2 mL, 2.5 M) under N₂ at −60° C. Stirredfor 1 h, Compound 8C (3 g, 11.4 mmol) in THF (10 mL) was added to themixture. After stirring for an additional 3 h at rt, the mixture wasdiluted with sat. aq. NH₄Cl (40 mL), extracted with ethyl acetate (50mL×2), washed with brine (100 mL×2), and then evaporated to give a crudeproduct, which was purified by silica gel column chromatography (ethylacetate in petroleum ether, 30% v/v) to yield Compound 8D (1.8 g, yield41%) as colorless oil. LC-MS (m/z): 390 [M+1]⁺.

A solution of Compound 8D (0.39 g, 1 mmol) in THF (10 mL) and 1 N aq HCl(2 mL) was stirred at rt for 5 h. The mixture was quenched with water(10 mL), extracted with ethyl acetate (20 mL×2), washed with brine (30mL×2), and evaporated to remove solvents. The crude product was purifiedby silica gel column chromatography (ethyl acetate in petroleum ether,50% v/v) to give Compound 8E (283 mg, yield 81%) as a colorless oil.LC-MS (m/z): 350 [M+1]⁺.

To a solution of Compound 8E (1 g, 2.9 mmol) in THF (25 mL) was addedtriethylamine (0.44 g, 4.4 mmol) and MsCl (0.4 g, 3.5 mmol) under N₂ at−40° C. The mixture was stirred at this temperature for 3 h beforequenched with water (40 mL). It was extracted with ethyl acetate (50mL×3), washed with brine (100 mL×2), and evaporated to give a crudeproduct, which was purified by silica gel column chromatography (ethylacetate in petroleum ether, 50% v/v) to yield Compound 8F (0.85 g, yield69%) as a colorless oil. LC-MS (m/z): 410 [M−17]⁺.

To a solution of Compound 8F (0.8 g, 2.3 mmol) in THF (25 mL) was addedpyrrolidine (1.5 g, 21 mmol). The mixture was stirred at 60° C.overnight, quenched with water (40 mL), extracted with ethyl acetate (50mL×3), washed with brine (100 mL×2), and evaporated to remove solvents.The crude product was purified by column chromatography on silica gel(ethyl acetate in petroleum ether, 50% v/v) to give Compound 8G (0.5 g,54%) as colorless oil. LC-MS (m/z): 403 [M+1]⁺.

A solution of Compound 8G (0.5 g, 1.2 mmol) and LiOH.H₂O (157 mg, 3.6mmol) in ethanol (20 mL) was heated to reflux overnight. The mixture wasquenched with water (40 mL), extracted with ethyl acetate (50 mL×3),washed with brine (100 mL×2), and evaporated to yield Compound 8H (0.3g, 93%) as a colorless oil. LC-MS (m/z): 269 [M+1]⁺.

To a solution of Compound 8H (0.2 g, 0.75 mmol) in dichloromethane (15mL) was added Compound 1H (191 mg, 0.9 mmol), EDCI (216 mg, 1.13 mmol),HOBt (152 mg, 1.13 mmol). The mixture was stirred at rt overnight,quenched with water (20 mL), extracted with DCM (20 mL×2), washed withbrine (50 mL×2), and evaporated. The crude product was purified byprep-HPLC to give 81 and followed by chiral-prep-HPLC to afford twoisomers 8J (5 mg) as a white solid and 8K (105 mg) as a white solid. For8J: LC-MS (m/z): 463 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.87 (m, 4H), 2.80 (m, 3H), 2.86 (m, 2H),2.96 (m, 3H), 3.10 (m, 3H), 3.72 (s, 3H), 3.81 (s, 1H), 4.34 (s, 1H),5.46 (s, 1H), 6.80 (m, 1H), 6.96 (m, 2H), 7.14 (m, 5H). For 8K: LC-MS(m/z): 463 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.84 (s, 4H), 2.80 (m, 7H), 3.02 (m, 3H), 3.18 (m, 1H), 3.81 (s,3H), 4.21 (s, 1H), 5.16 (m, 1H), 6.81 (m, 1H), 6.94 (m, 1H), 7.16 (m,5H).

Example 9

To a solution of Compound 9A (2.18 g, 15 mmol) in DCM (50 mL) was addedDMP (7.44 g, 18 mmol). The mixture was stirred at rt for 2 h, followedby filtration. The filtrate was washed with sat. aq. NaHCO₃ (50 mL×2),extracted with DCM (50 mL×2), washed with brine (1×50 mL), dried overNa₂SO₄, concentrated, and purified by column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 9B (1.2g, yield 56%) as a white solid. LC-MS (m/z): 148 [M+1]⁺; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 3.17 (m, 1H), 3.38 (m, 4H),7.09 (m, 1H), 7.53 (d, J=8.0 Hz, 1H), 8.39 (d, J=4.4 Hz, 1H), 9.82 (s,1H).

Compound 9B (1.2 g, 8.2 mmol) was added to a solution of sodiummetabisulfate (1.55 g, 8.2 mmol) in water (35 mL). The mixture wasvigorously stirred for 2 h at rt before the addition of NaCN (800 mg, 16mmol). Stirred overnight, the mixture was diluted with water (30 mL) andTHF (10 mL). The mixture was extracted with ethyl acetate (100 mL×2),washed with brine (100 mL×1), dried over Na₂SO₄, and concentrated togive Compound 9C (1.15 g, yield 81%) as a white solid. LC-MS (m/z): 175[M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm)2.86 (m, 3H), 3.08 (m, 2H), 4.62 (m, 1H), 6.63 (t, J=3.2 Hz, 1H), 7.13(t, J=7.2 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 8.29 (d, J=4.8 Hz, 1H).

A solution of Compound 9C (1.15 g, 6.6 mmol) in EtOH (20 mL) was bubbledwith a gentle stream of HCl (gas) (dried over conc. H₂SO₄) for 5 h at 0°C. The mixture was added water (20 mL), stirred at rt for 2 h, and thenadjusted pH to 7 with dilute NaOH (2M). It was extracted with DCM (50mL×2), washed with brine (50 mL×1), dried over Na₂SO₄, concentrated, andpurified by silica gel column chromatography (ethyl acetate in petroleumether, 50% v/v) to yield Compound 9D (1 g, yield 69%) as a colorlessoil. LC-MS (m/z): 222 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.29 (m, 3H), 3.055 (m, 5H), 4.24 (m, 3H),7.03 (m, 1H), 7.46 (m, 1H), 8.33 (d, J=4.4 Hz, 1H)

To a solution of Compound 9D (500 mg, 2.26 mmol) in DCM (20 mL) wasadded DAST (1.1 g, 6.78 mmol) at 0° C., then the mixture was stirred atrt overnight. The mixture was poured into ice-water, added sat. aqNaHCO₃ (20 mL), extracted with DCM (50 mL×2), washed with brine (50mL×1), dried over Na₂SO₄ and evaporated. The crude product was purifiedby silica gel column chromatography (ethyl acetate in petroleum ether,50% v/v) to render Compound 9E (170 mg, yield 34%) as a colorless oil.LC-MS (m/z): 224 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 1.29 (t, J=7.2 Hz, 3H), 3.12 (m, 5H), 4.26 (q, J=7.2 Hz,2H), 5.01 (m, 1H), 7.06 (m, 1H), 7.49 (d, J=7.6 Hz, 1H), 8.35 (d, J=5.2Hz, 1H).

To a solution of Compound 9E (170 mg, 0.76 mmol) in EtOH (5 mL) wasadded LiOH (96 mg, 2.29 mmol) in water (5 mL). The mixture was stirredat rt overnight and concentrated to remove EtOH. After adjusted pH to 7with diluted aq HCl, a lyophilization of the solution led to Compound 9F(148 mg, crude), which was used for the next step without furtherpurification. LC-MS (m/z): 196 [M+1]⁺.

A mixture of Compound 9F (100 mg, 0.51 mmol), EDCI (148 mg, 0.77 mmol),HOBt (105 mg, 0.77 mmol), DIPEA (198 mg, 1.54 mmol), Intermediate A (142mg, 0.51 mmol) in THF (20 mL) was stirred at rt overnight. Afteraddition of aq sat. NaHCO₃, the mixture was extracted with ethyl acetate(50 mL×2), washed with brine (50 mL×1), dried over Na₂SO₄, andconcentrated. The crude product was purified by prep-HPLC to giveCompound 9 (39 mg, yield 18%) as a white solid. LC-MS (m/z): 456 [M+1]⁺;¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.73 (s,4H), 2.86 (m, 11H), 4.16 (m, 5H), 4.76 (s, 0.5H), 4.87 (m, 1H), 4.98 (s,0.5H), 6.75 (m, 4H), 6.95 (m, 1H), 7.35 (m, 1H), 8.24 (m, 1H).

Example 10

A solution of 1, 4-dichloro-2-nitrobenzene (5 g, 26 mmol) in 30%methylamine alcohol solution (50 mL) was stirred at 50° C. for 4 h. Themixture was quenched with water (50 mL) and extracted with ethyl acetate(80 mL×3). The organic layer was washed with brine (150 mL×2) and thenevaporated to give Compound 10A (4 g, yield 84%) as a red solid. LC-MS(m/z): 187 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.95 (d, J=4.8 Hz, 3H), 7.04 (d, J=9.2 Hz, 1H), 7.59 (d, J=9.2 Hz,1H), 8.05 (s, 1H), 8.24 (s, 1H).

To a solution of Compound 10A (3 g, 16 mmol) in ethanol (100 mL) wasadded 10 N aq HCl (2 mL) and Fe (9 g, 0.16 mmol). The mixture wasstirred at 80° C. overnight. After filtration, the filtrate was washedwith 3 N aq NaOH (50 mL), extracted with ethyl acetate (100 mL×2), anddried over Na₂SO₄. Filtration and solvent evaporation led to crudeCompound 10B (2.7 g, crude) as a red solid, which was used to next stepwithout purified. LC-MS (m/z): 157 [M+1]⁺.

To a solution of Compound 10B (2.5 g, 16 mmol) in methanol (50 mL) wasadded triethoxymethane (2.8 g, 19 mmol) and sulfamic acid (155 mg, 1.6mmol). The mixture was stirred at rt for 5 h. After removal of solvents,the mixture was diluted with water (30 mL) and extracted with ethylacetate (50 mL×3). The organic layer was dried over Na₂SO₄. Filtrationand evaporation of solvents gave a crude product Compound 10C (2.3 g,crude) as a red solid, which was used to next step without purification.LC-MS (m/z): 167 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 3.84 (s, 3H), 7.30 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.8 Hz,1H), 7.70 (s, 1H), 8.25 (s, 1H).

Ethyl oxalyl chloride (2.7 g, 20 mmol) was added dropwise over 20 minsto a stirred solution of Compound 10C (2.5 g, 15 mmol) indichloromethane (60 mL) at −20° C. Then DIPEA (3.9 g, 30 mmol) was addedand the mixture was warmed to rt and kept stirring overnight. Themixture was quenched with water (50 mL) and extracted withdichloromethane (50 mL×2). The organic layer was dried over Na₂SO₄before filtered and concentrated, giving a crude product. The crudeproduct was purified by column chromatography on silica gel (ethylacetate in petroleum ether, 30% v/v) to give Compound 10D (3.3 g, yield83%) as yellow solid. LC-MS (m/z): 267 [M+1]⁺.

To a solution of Compound 10D (1.5 g, 5.6 mmol) in dichloromethane (30mL) was added DAST (2.7 g, 17 mmol). The mixture was stirred at rtovernight, quenched with water (30 mL), and extracted withdichloromethane (50 mL×2). After dried over Na₂SO₄, the organic layerwas filtered and concentrated to give the crude product Compound 10E(0.9 g, crude) as a colorless oil, which was used for the next stepwithout purification. LC-MS (m/z): 289 [M+1]⁺.

To a solution of Compound 10E (1 g, 3.5 mmol) in methanol (20 mL) andH₂O (10 mL) was added LiOH.H₂O (294 mg, 7 mmol). The mixture was stirredat rt for 5 h, quenched with water (30 mL), and extracted with ethylacetate (50 mL×2). The organic layer was dried over Na₂SO₄. Filtrationand removal of solvents led to the crude product Compound 10F (0.4 g,crude) as a colorless oil, which was used for the next step withoutpurification. LC-MS (m/z): 261 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) δ (ppm)3.97 (s, 3H), 7.47 (d, J=10.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.86 (s,1H).

To a solution of Intermediate A (0.16 g, 0.58 mmol) in dichloromethane(15 mL) was added Compound 10F (150 mg, 0.58 mmol), EDCI (167 mg, 0.87mmol), HOBt (116 mg, 0.87 mmol). The mixture was stirred at rtovernight, quenched with water (20 mL), extracted with dichloromethane(20 mL×2), washed with brine (50 mL×2), and evaporated. The crudeproduct was purified by prep-HPLC to afford Compound 10 (29 mg, yield9.6%) as a white solid. LC-MS (m/z): 521 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 1.95 (m, 4H), 3.47 (m, 6H), 3.89 (s,3H), 4.16 (s, 4H), 4.42 (s, 1H), 4.69 (s, 1H), 5.91 (s, 1H), 6.57 (d,J=8.8 Hz, 1H), 6.79 (d, J=10.4 Hz, 1H), 6.81 (s, 1H), 7.50 (d, J=11.2Hz, 1H), 7.80 (d, J=10.8 Hz, 2H), 8.96 (d, J=9.2 Hz, 1H), 9.37 (s, 1H).

Example 11

A mixture of 4-chlorophenol (10 g, 78 mmol), 2-bromo-1,1-dimethoxyethane(13.1 g, 78 mmol), K₂CO₃ (14 g, 101 mmol), KI (100 mg) in DMF (50 mL)was stirred at reflux for 3 h. The mixture was cooled to rt andfiltered. The filtrate was added water (200 mL), extracted with ethylacetate (100 mL×2), washed with water (100 mL×3), brine (100 mL×1),dried over Na₂SO₄, concentrated, and purified by column chromatographyon silica gel (ethyl acetate in petroleum ether, 10% v/v) to yieldCompound 11A (15 g, yield 89%) as a colorless liquid. ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 3.45 (s, 6H), 3.96 (d, J=5.2Hz, 2H), 4.70 (t, J=5.6 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8Hz, 2H).

A solution of polyphosphoric acid (90 g) in toluene was heated to 90° C.To this solution was added Compound 11A (15.4 g, 71 mmol) in toluene (20mL), followed by stirring at 90° C. for 3 h. The mixture was poured intoice and stirred for 30 min. It was extracted with ethyl acetate (2×100mL), washed with brine (100 mL×1), dried over Na₂SO₄, concentrated andpurified by column chromatography on silica gel (petroleum ether, 100%v/v) to yield Compound 11B (4.5 g, yield 50%) as a red liquid. ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 6.72 (m, 1H), 7.24(dd, J₁,J₂=8.8, 2.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.56 (d, J=2.0 Hz,1H), 7.63 (d, J=2.4 Hz, 1H).

To a solution of Compound 11B (4.5 g, 30 mmol) in THF (20 mL) was addedn-BuLi (14 mL) at −78° C. under N₂. Stirred for 30 min, to the mixturewas added diethyl oxalate (10.8 g, 74 mmol). The mixture was stirred at−78° C. for 1 h before the addition of aq sat. NH₄Cl. It was extractedwith ethyl acetate (50 mL×2), washed with sat. NaHCO₃ (50 mL×2), brine(50 mL×1), dried over Na₂SO₄, concentrated and purified by silica gelcolumn chromatography (ethyl acetate in petroleum ether, 20% v/v) togive Compound 11C (3.5 g, yield 47%) as a yellow solid. ¹H NMR (DMSO-d₆,400 MHz) major characteristic peaks: δ (ppm) 1.37 (t, J=6.8 Hz, 3H),4.41 (q, J=6.8 Hz, 2H), 7.64 (m, 1H), 7.82 (d, J=8.8 Hz, 1H), 8.03 (d,J=2.4 Hz, 1H), 8.19 (s, 1H).

To a solution of Compound 11C (1 g, 3.95 mmol) in DCM (50 mL) was addedDAST (3.18 g, 18 mmol) at 0° C., then the mixture was stirred at rtovernight. The reaction was quenched by addition of ice-water and sat.aq NaHCO₃ (20 mL). It was then extracted with DCM (50 mL×2), washed withbrine (50 mL×1), dried over Na₂SO₄, and evaporated to remove solvents.The crude product was purified by silica gel column chromatography(ethyl acetate in petroleum ether, 10% v/v) to yield Compound 11D (700mg, yield 65%) as a yellow liquid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.37 (t, J=6.8 Hz, 3H), 4.41 (q, J=6.8 Hz,2H), 7.10 (s, 1H), 7.36 (m, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.62 (d, J=2.0Hz, 1H).

To a solution of Compound 11D (120 mg, 0.44 mmol) in EtOH (5 mL) wasadded LiOH (46 mg, 1.09 mmol) in water (5 mL). The mixture was stirredat rt overnight, followed by removal of EtOH. It was adjusted to pH 7with diluted HCl and freeze-dried to give Compound 11E (100 mg, crude)which was used for the next step without further purification. LC-MS(m/z): 245 [M−1]⁻.

A mixture of Compound 11E (100 mg, 0.41 mmol), EDCI (117 mg, 0.61 mmol),HOBt (83 mg, 0.61 mmol), Intermediate A (115 mg, 0.41 mmol) in DCM (20mL) was stirred at rt overnight. The reaction was quenched by additionof sat. NaHCO₃. The resulting mixture was extracted with DCM (50 mL×2),washed with brine (50 mL×1), dried over Na₂SO₄, and evaporated todryness. The crude product was purified by prep-HPLC to give Compound 11(49 mg, yield 24%) as a white solid. LC-MS (m/z): 507 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.13 (s, 4H), 2.91(m, 2H), 3.48 (s, 2H), 3.84 (s, 2H), 4.15 (m, 4H), 4.46 (m, 1H), 5.13(s, 1H), 6.77 (s, 3H), 6.84 (s, 1H), 7.35 (m, 1H), 7.42 (d, J=8.8 Hz,1H), 7.58 (d, J=2.0 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 11.68 (s, 1H).

Example 12

To a mixture of Intermediate B (300 mg, 1 mmol) in DCM (15 mL) was addedEDCI (400 mg, 2 mmol), HOBt (264 mg, 2 mmol) and Compound 1H (300 mg,1.5 mmol) and stirred at rt overnight. The reaction mixture was pouredinto water (50 mL), extracted with DCM (20 mL×3), dried over anhydrousNa₂SO₄, and purified by prep-HPLC to afford a crude product 12A (100 mg,yield 20%) as a white solid. The chiral resolution on Compound 12A wasachieved using chiral-prep-HPLC to give Compound 12B (70 mg) and 12 (1.2mg). For Compound 12B, LCMS: 491 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.82 (m, 4H), 2.82 (m, 7H), 3.04 (m, 3H),3.19 (m, 1H), 4.16 (m, 1H), 4.26 (m, 4H), 5.05 (m, 1H), 6.56 (d, J=10.8Hz, 1H), 6.69 (m, 1H), 7.06 (d, J=7.2 Hz, 1H), 7.16 (m, 4H). ForCompound 12, LCMS: 491 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.23 (m, 4H), 2.67 (m, 1H), 2.82 (m, 1H),2.97 (m, 2H), 3.12 (m, 2H), 3.65 (m, 1H), 3.81 (m, 1H), 3.89 (m, 1H),4.03 (m, 1H), 4.12 (m, 1H), 4.18 (m, 1H), 4.47 (m, 1H), 5.43 (m, 1H),6.60 (d, J=11.2 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.16 (m, 5H).

Example 13

To a solution of Compound 13A (2.00 g, 10 mmol) in DCM (50 mL) was addedDMP (7.44 g, 18 mmol). The mixture was stirred at rt for 2 h andfiltered. The filtrate was washed with sat. aq NaHCO₃ (50 mL×2),extracted with DCM (50 mL×2), washed with brine (50 mL), dried overNa₂SO₄, concentrated, and purified by silica gel column chromatography(ethyl acetate in petroleum ether, 10% v/v) to get Compound 13B (1.2 g,yield 56%) as a white solid. LC-MS (m/z): 199 [M+1]⁺.

Compound 13B (1.13 g, 5 mmol) was added to a solution of sodiummetabisulfate (1.55 g, 8.2 mmol) in water (35 mL). The mixture wasvigorously stirred for 2 h at rt, before the addition of NaCN (800 mg,16 mmol). After stirred overnight, the reaction mixture was poured to amixture of water (30 mL) and THF (10 mL). It was then extracted withethyl acetate (100 mL×2), washed with brine (00 mL), dried over Na₂SO₄,and concentrated to give Compound 13C (1.15 g, 81%) as a white solid.LC-MS (m/z): 226 [M+1]⁺.

To a solution of Compound 13C (1.15 g, 5 mmol) in EtOH (20 mL) wasbubbled with a gentle stream of HCl (gas) (dried over con. H₂SO₄) at 0°c. for 5 h. Water (20 mL) was added to the mixture and stirred at rt for2 h. It was adjusted to pH=7 with diluted NaOH (2M), extracted with DCM(50 mL×2), washed with brine (50 mL), dried over Na₂SO₄, concentrated,and purified by silica gel column chromatography (ethyl acetate inpetroleum ether, 50% v/v) to get Compound 13D (1 g, yield 69%) as acolorless oil. LC-MS (m/z): 273 [M+1]⁺.

To a solution of Compound 13D (2.72 g, 10 mmol) in DCM (50 mL) was addedDMP (7.44 g, 18 mmol). The mixture was stirred at rt for 2 h andfiltered. The filtrate was washed with sat. aq NaHCO₃ (50 mL×2),extracted with DCM (50 mL×2), washed with brine (50 mL), dried overNa₂SO₄, concentrated, and purified by column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to get Compound 13E (1.2g, yield 56%) as a white solid. LC-MS (m/z): 271 [M+1]⁺.

To a solution of Compound 13E (540 mg, 2 mmol) in DCM (20 mL) was addedDAST (1.1 g, 6.78 mmol) at 0° C., then the mixture was stirred at rtovernight. The reaction mixture was quenched by pouring into ice-water.After neutralized with sat. NaHCO₃ (20 mL), the mixture was extractedwith DCM (2×50 mL), washed with brine (1×50 mL), dried over Na₂SO₄, andevaporated to dryness. The crude product was purified by silica gelcolumn chromatography (ethyl acetate in petroleum ether, 50% v/v) toyield Compound 13F (170 mg, yield 34%) as a colorless oil. LC-MS (m/z):293 [M+1]⁺.

To a solution of Compound 13F (293 mg, 1 mmol) in EtOH (5 mL) was addedLiOH (96 mg, 2.29 mmol) in water (5 mL). The mixture was stirred at rtovernight, concentrated to remove EtOH, and adjusted to pH 7 withdiluted HCl. It was then lyophilized to give Compound 13G (148 mg,crude), which was used for the next step without further purification.LC-MS (m/z): 265 [M+1]⁺.

A mixture of Compound 13G (132 mg, 0.51 mmol), EDCI (148 mg, 0.77 mmol),HOBt (105 mg, 0.77 mmol), DIPEA (198 mg, 1.54 mmol), Intermediate A (142mg, 0.51 mmol) in THF (20 mL) was stirred at rt overnight. After theaddition of sat. aq NaHCO₃, the mixture was extracted with ethyl acetate(50 mL×2), washed with brine (50 mL), dried over Na₂SO₄, and evaporatedto dryness. The crude product was purified by prep-HPLC to give Compound13 (39 mg, yield 18%) as a white solid. LC-MS (m/z): 525 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.84 (m, 4H), 2.75(m, 4H), 3.03 (m, 6H), 4.22 (m, 6H), 5.11 (m, 1H), 6.90 (m, 4H), 7.85(s, 2H), 8.76 (s, 2H).

Example 14

To a solution of Compound 14A (1.21 g, 8 mmol) in THF (20 mL) was addedNaH (480 mg, 12 mmol) under N₂ atmosphere. The mixture was stirred at 0°C. for 1 h. CH₃I (0.47 mL, 16 mmol) was added. The mixture was stirredat 25° C. for additional 2 h. It was diluted with NH₄Cl (30 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (60 mL), dried over Na₂SO₄, and concentrated to give a crudeproduct, which was purified by column chromatography on silica gel(ethyl acetate in petroleum 10% v/v) to yield Compound 14B (1.2 g, yield90%) as a red oil. LCMS (m/z): 166 [M+1]⁺. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.76 (s, 3H), 6.40 (d, J=3.2 Hz, 1H), 7.05(d, J=3.2 Hz, 1H), 7.16 (dd, J=1.6, 8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H),7.57 (d, J=1.6 Hz, 1H).

To a solution of Compound 14B (1.04 g, 6 mmol) in THF (20 mL) was addedn-BuLi (3 ml, 8 mmol) at −78° C. under the protection of nitrogen. Thenit was allowed to warm up to rt over one hour. At this point, diethyloxalate (2.1 mL, 16 mmol) was added to the mixture at −78° C. and thenit was allowed to warm up to rt over one hour. The mixture was quenchedwith sat. aq NH₄Cl. The organic phase was washed with brine, dried overanhydrous Na₂SO₄, and purified by silica gel column chromatography(ethyl acetate in petroleum 3% to 10% v/v) to afford Compound 14C (1.38g, yield 86%) as a yellow solid. LCMS (m/z): 266 [M+1]⁺; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 1.45 (t, J=7.2 Hz, 3H),4.08 (s, 3H), 4.45 (q, J=7.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.39 (dd,J=1.6, 8.4 Hz, 1H), 7.53 (s, 1H), 7.69 (d, J=1.6 Hz, 1H).

To a solution of Compound 14C (530 mg, 2 mmol) in DCM (20 mL) was addedDAST (1.6 mL, 12 mmol) at 0° C. under N₂ and stirred at 25° C.overnight. It was poured into 50 mL of ice-water and extracted with DCM(20 mL×3). The combined organic phase was washed with brine, and driedover anhydrous Na₂SO₄, and purified by silica gel column chromatography(ethyl acetate in petroleum, 10% v/v) to yield Compound 14D (195 mg,yield 33%) as yellow oil. LCMS (m/z): 288[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 1.37 (t, J=8.8 Hz, 3H), 3.86 (s,3H), 4.40 (q, J=8.8 Hz, 2H), 6.73 (s, 1H), 7.28 (s, 2H), 7.60 (s, 1H).

To a solution of Compound 14D (195 mg, 0.68 mmol) in THF/MeOH/water (6mL, 1:1:1, v/v/) was added LiOH.H₂O (34 mg, 0.81 mmol). The mixture wasstirred at 25° C. for 1 h. After removal of the solvents, it was adjustpH to 6 with 1N HCl. The mixture was dissolved ethyl acetate (100 mL),washed with water, brine, and dried over anhydrous Na₂SO₄. Removal ofsolvent by evaporation led to a crude product Compound 14E (140 mg,yield 80%) was got as a yellow solid, which was used for the next stepwithout purification. LCMS (m/z): 260 [M+1]⁺.

To a mixture of Compound 14E (70 mg, 0.27 mmol) in DCM (20 mL) was addedEDCI (78 mg, 0.40 mmol), HOBt (54 mg, 0.40 mmol) and Intermediate A (66mg, 0.27 mmol) and stirred at 25° C. for overnight. The reaction wasquenched with addition of water (10 mL). The mixture was extracted withDCM (20 mL×3), dried over anhydrous Na₂SO₄, and purified by prep-HPLC togive a trifluoroacetic acid salt of Compound 14 (80 mg, yield 56%) as acolorless solid. LCMS (m/z): 529 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.13 (m, 4H), 2.70-2.91 (m, 2H), 3.06-3.43(s, 2H), 3.73 (s, 3H), 3.86 (s, 2H), 4.00-4.09 (m, 1H), 4.09-4.21 (m,2H), 4.49 (s, 1H), 5.17 (s, 1H), 6.09 (s, 1H), 6.76-6.80 (m, 2H), 6.83(s, 1H), 7.23-7.24 (m, 2H), 7.54 (s, 2H).

Example 15

A mixture of Compound 15A (12.64 g, 78 mmol),2-bromo-1,1-dimethoxyethane (13.6 g, 79 mmol), K₂CO₃ (14 g, 101 mmol),KI (100 mg) in DMF (50 mL) was stirred at reflux for 3 h, and thencooled to rt, and filtered. The filtrate was diluted with water (200mL), extracted with ethyl acetate (100 mL×2), washed with water (100mL×3), brine (100 mL×1), dried over Na₂SO₄, concentrated, and purifiedby silica gel column chromatography (ethyl acetate in petroleum ether,10% v/v) to yield Compound 15B (17.2 g, yield 88%) as a red liquid.¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 3.49 (s,6H), 4.02 (d, J=5.2 Hz, 2H), 4.73 (t, J=5.6 Hz, 1H), 6.86 (d, J=8.8 Hz,1H), 7.15-7.18 (dd, J=2.8, 8.8 Hz, 1H), 7.36 (d, J=2.8 Hz, 1H).

A solution of polyphosphoric acid (90 g) in toluene was stirred to 90°C., then to the solution was added Compound 15B (15 g, 60 mmol) intoluene (20 mL). The mixture was stirred at 90° C. for 3 h before it waspoured into ice and stirred for 30 min. It was then extracted with ethylacetate (100 mL×2), washed with brine (100 mL×1), dried over Na₂SO₄,concentrated, and purified by silica gel column chromatography(petroleum ether, 100% v/v) to give Compound 15C (2.6 g, yield 23%) as awhite solid. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)6.76 (d, J=2.4 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H),7.69 (d, J=2.4 Hz, 1H).

To a solution of Compound 15C (1.6 g, 8.6 mmol) in THF (10 mL) was addedn-BuLi (4.2 mL) at −78° C. under N₂. After stirred for 30 min, to themixture was added diethyl oxalate (10.8 g, 74 mmol). It was stirred at−78° C. for 1 h before it was quenched by addition of aq sat. NH₄Cl. Themixture was sequentially extracted with ethyl acetate (50 mL×2), washedwith sat. NaHCO₃ (50 mL×2), brine (50 mL×1), dried over Na₂SO₄,concentrated, and purified by silica gel column chromatography (ethylacetate in petroleum ether, 20% v/v) to yield Compound 15D (1.64 g,yield 67%) as a yellow solid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.46 (t, J=7.2 Hz, 3H), 4.48 (q, J=7.2 Hz,2H), 7.54 (m, 1H), 7.66 (d, J=1.6 Hz, 1H), 8.04 (s, 1H).

To a solution of Compound 15D (500 mg, 1.75 mmol) in DCM (15 mL) wasadded DAST (1.15 g, 8.74 mmol) at 0° C. The mixture was stirred at rtovernight before it was poured into ice-water, and followed by additionof aq sat. aq NaHCO₃ (20 mL). The resulted mixture was extracted withDCM (50 mL×2), washed with brine (50 mL×1), dried over Na₂SO₄, andconcentrated to give a crude product, which was purified by silica gelcolumn chromatography (ethyl acetate in petroleum ether, 10% v/v) toafford Compound 15E (269 mg, yield 50%) as a red liquid. ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 1.37 (t, J=6.8 Hz, 3H),4.44 (q, J=7.2 Hz, 2H), 7.14 (s, 1H), 7.41 (m, 1H), 7.54 (m, 1H).

To a solution of Compound 15E (260 mg, 0.88 mmol) in EtOH (0.5 mL) wasadded LiOH (46 mg, 1.09 mmol) in water (0.5 mL). The mixture was stirredat rt overnight, evaporated to remove EtOH, and neutralized with dilutedHCl. This aqueous solution was lyophilized to yield a crude Compound 15F(193 mg), which was used for the next step without further purification.LC-MS (m/z): 279 [M−1]⁻.

A mixture of Compound 15F (70 mg, 0.25 mmol), EDCI.HCl (71 mg, 0.37mmol), HOBt (50 mg, 0.37 mmol), Intermediate A (61 mg, 0.25 mmol) in DCM(10 mL) was stirred at 28° C. overnight. The reaction was quenched byaddition of aq sat. NaHCO₃. The mixture was extracted with DCM (50mL×2), washed with brine (50 mL×1), dried over Na₂SO₄, and concentratedto give a crude product, which was purified by prep-HPLC to affordCompound 15 (46.3 mg, yield 23%) as a white solid. LC-MS (m/z): 541[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)2.12-2.17 (m, 4H), 2.93-2.99 (m, 2H), 3.45-3.55 (m, 2H), 3.82-3.92 (m,3H), 4.10-4.16 (m, 4H), 4.52 (s, 1H), 5.05 (s, 1H), 6.70-6.83 (m, 4H),7.40 (s, 1H), 7.49 (s, 1H), 7.94-7.96 (d, J=8.0 Hz, 1H), 11.53 (s, 1H).

Example 16

The mixture of Compound 16A (4.10 g, 19.25 mmol) in DCM (100 mL) wasadded DMP (9.79 g, 23.09 mmol) at rt. After stirred at rt for 1 h themixture was diluted with ethyl acetate (200 mL), filtered to removesolid, washed with water and brine, and purified by silica gelchromatography (ethyl acetate in petroleum ether, 20% v/v) to giveCompound 16B (3.10 g, yield 76%) as a colorless oil. LCMS (m/z): 212[M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.90(t, J=9.2 Hz, 2H), 3.06 (t, J=9.2 Hz, 2H), 7.25-7.32 (m, 2H), 7.43 (t,J=12.8 Hz, 1H), 7.78-7.93 (m, 4H), 8.74 (s, 1H), 9.86 (s, 1H).

A mixture of Compound 16B (3.00 g, 14.22 mmol) and 2NaO₅S₂ (2.70 g,14.22 mmol) in H₂O/dioxane (50/10 mL) was stirred at rt for 2 h. Afterthe addition of NaCN (1.39 g, 28.43 mmol), the mixture was stirred at rtovernight. It was diluted with ethyl acetate (200 mL), washed with waterand brine, and purified by silica gel column chromatography (ethylacetate in petroleum ether, 50% v/v) to yield Compound 16C (2.00 g,yield 59%) as a colorless oil. LCMS (m/z): 239 [M+1]⁺; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 2.05-2.26 (m, 2H),2.83-2.96 (m, 2H), 4.36 (t, J=6.8 Hz, 1H), 4.97 (s, 1H), 7.22-7.31 (m,2H), 7.41 (t, J=7.6 Hz, 1H), 7.69-7.82 (m, 4H), 8.68 (s, 1H).

A solution of Compound 16C (2.00 g, 8.40 mmol) in MeOH (50 mL) wasstirred at rt for 6 h with HCl gas bubbling. The reaction was quenchedwith H₂O (10 mL) and stirred at rt for 1 h. It was diluted with ethylacetate (150 mL), washed with water and brine, dried with anhydrousNaSO₄, and evaporated to give Compound 16D (1.90 g, yield 83%) ascolorless oil. LCMS (m/z): 272 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.96-2.06 (m, 1H), 2.14-2.23 (m, 1H),2.83-2.90 (m, 2H), 3.75 (s, 3H), 4.21-4.24 (m, 1H), 7.21-7.29 (m, 1H),7.40 (t, J=7.6 Hz, 1H), 7.22-7.80 (m, 3H), 7.87 (s, 1H), 8.70 (s, 1H).

To a solution of Compound 16D (800 mg, 2.95 mmol) in DCM (20 mL) wasadded DMP (1.50 g, 3.54 mmol). The mixture was stirred at rt for 2 h. Itwas then diluted with ethyl acetate (150 mL), filtered to remove solid,washed with water and brine, dried with anhydrous Na₂SO₄, and purifiedby silica gel column chromatography (ethyl acetate in PE, 30% v/v) toyield Compound 16E (300 mg, yield 38%) as a colorless oil. LCMS (m/z):270 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)3.07 (t, J=7.2 Hz, 2H), 3.28 (t, J=7.2 Hz, 2H), 3.86 (m, 3H), 7.25-7.35(m, 2H), 7.43 (t, J=7.2 Hz, 1H), 7.78-7.93 (m, 4H), 8.74 (s, 1H).

To a solution of Compound 16E (400 mg, 1.48 mmol) in DCM (15 mL) wasadded DAST (1.23 g, 7.43 mmol) at rt. The mixture was stirred at rtovernight. It was then diluted with ethyl acetate (150 mL), washed withsaturated NaHCO₃, waster and brine, purified by silica gel columnchromatography (ethyl acetate in petroleum ether, 40% v/v) to affordCompound 16F (120 mg, yield 28%) as a white solid. LCMS (m/z): 292[M+1]⁺.

A mixture of Compound 16F (120 mg, 0.41 mmol) and LiOH.H₂O (52 mg, 1.24mmol) in THF/MeOH/H₂O (5/5/2 mL) was stirred at rt for 2 h. It wasadjusted to pH 6 with 1 M HCl and purified by prep-HPLC to give Compound16G (80 mg, yield 70%) as white solid. LCMS (m/z): 278 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.40-2.53 (m, 2H),2.89-2.93 (m, 2H), 7.26-7.37 (m, 2H), 7.42 (t, J=7.2 Hz, 1H), 7.73-7.88(m, 4H), 8.72 (s, 1H).

A solution of Intermediate A (80 mg, 0.29 mmol), Compound 16G (80 mg,0.29 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) in DCM(5 mL) was stirred at rt overnight. It was then diluted with ethylacetate (150 mL), washed with water and brine, and purified by prep-HPLCto afford Compound 16 (50 mg, yield 32%) as a white solid. LCMS (m/z):538 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)1.58 (br s, 2H), 1.86 (s, 4H), 2.21-2.42 (m, 3H), 2.56-2.64 (m, 1H),2.75-2.85 (m, 3H), 3.02 (s, 2H), 3.88-4.06 (m, 4H), 4.21 (s, 1H), 5.12(s, 1H), 6.78-6.87 (m, 4H), 7.14 (d, J=7.6, 1H), 7.39 (t, J=7.6 Hz, 1H),7.72-7.82 (m, 4H), 8.69 (s, 1H).

Example 17

To a solution of Compound 17A (3.12 g, 20 mmol) in anhydroustetrahydrofuran (80 mL) was added zinc (2.1 g, 26 mmol). The mixture washeated at 75° C. under N₂ atmosphere and ethyl2-bromo-2,2-difluoroacetate (3.2 mL, 29 mmol) was slowly added. Themixture was heated under the same conditions for 2 h. After cooling, itwas filtered. The filtrate was concentrated to give a crude productwhich was purified by column chromatography on silica gel (ethyl acetatein petroleum 5% to 20% v/v) to yield Compound 17B (3.9 g, yield 70%) asa white solid. LCMS (m/z): 281 [M+1]⁺. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.26 (t, J=7.2 Hz, 3H), 4.30 (q, J=7.2 Hz,2H), 5.34 (q, J=8 Hz, 1H), 7.50-7.56 (m, 3H), 7.83-7.88 (m, 3 3H), 7.91(s, 1H)

To a solution of Compound 17B (280 mg, 1 mmol) in DCM (20 mL) was addeddropwise N,N′-thiocarbonyldiimidazole (25.0 g, 126 mmol) in DCM (10 mL)at 72° C. After stirring for 3 h, the reaction mixture was cooled to rtand concentrated in vacuum to give a crude product. It was purified bysilica gel column chromatography (ethyl acetate in petroleum 5% to 20%v/v) to afford Compound 17C (310 mg, yield 79%) as a yellow oil. LCMS(m/z): 391 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.24 (t, J=7.2 Hz, 3H), 4.30 (q, J=7.2 Hz, 2H), 6.98 (m, 1H), 7.10(s, 1H), 7.53-7.55 (m, 3H), 7.70 (s, 1H), 7.84-7.90 (m, 3H), 7.94 (s,1H), 8.43 (s, 1H).

To a solution of n-Bu₃SnH (922 mg, 1.59 mmol) and AIBN (2 mg, cat.) inrefluxing toluene (10 ml) was added dropwise the Compound 17C (310 mg,0.79 mmol) in toluene (10 ml). After stirred for 3 h at 110° C., thereaction mixture was cooled to rt and concentrated in vacuum to give acrude product Compound 17D (500 mg, crude) as a yellow oil. It was usedfor the next step without purification. LCMS (m/z): 265 [M+1]⁺.

To a solution of Compound 17D (500 mg, 0.79 mmol) in THF/MeOH/water (3mL, 1:1:1, v/v/) was added LiOH.H₂O (60 mg, 1.5 mmol). The mixture wasstirred at 25° C. for 1 h. After the addition of water (20 mL), themixture was extracted with ethyl acetate (20 mL×2). The water phrase wasadjusted pH to 6 with 1 N HCl and extracted with ethyl acetate (20mL×2). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuum to give a crude product Compound 17E (169 mg,yield 80%) as a white solid. LCMS (m/z): 235 [M−1]⁻; ¹H-NMR (DMSO-d₆,400 MHz) major characteristic peaks: δ (ppm) 3.59 (t, J=17.2 Hz, 2H),7.42 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.82 (s, 1H), 7.90 (t, J=8Hz, 3H), 14.75 (s, 1H).

To a mixture of Compound 17E (67 mg, 0.25 mmol) in DCM (10 mL) was addedEDCI (72 mg, 0.38 mmol), HOBt (51 mg, 0.38 mmol) and Intermediate A (61mg, 0.25 mmol) and stirred at 25° C. overnight. After the addition ofwater (10 mL), the mixture was extracted with DCM (20 mL×3), dried overanhydrous Na₂SO₄, and purified by prep-HPLC to afford trifluoroaceticacid salt of Compound 17 (47 mg, yield 27%) as a white solid. LCMS(m/z): 496 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.62-2.03 (m, 4H), 2.53 (s, 1H), 2.95 (s, 1H), 3.33-3.56 (m, 4H),3.94 (s, 2H), 4.19 (s, 4H), 4.25 (s, 1H), 4.89 (s, 1H), 6.60 (d, J=8 Hz,1H), 6.71 (d, J=8 Hz, 1H), 6.78 (s, 1H), 7.34 (t, J=8 Hz, 2H), 7.48 (d,J=8 Hz, 2H), 7.70 (s, 1H), 7.77-7.83 (m, 3H), 11.31 (s, 1H).

Example 18

A mixture of Compound 18A (30 g, 184 mmol), 2-bromo-1,1-dimethoxyethane(37 g, 221 mmol), K₂CO₃ (38 g, 276 mmol), KI (600 mg) in DMF (150 mL)was stirred at reflux overnight. Cooling to rt, it was filtered. Thefiltrate was diluted with water (500 mL), extracted with ethyl acetate(250 mL×2), washed with water (250 mL×3) and brine (250 mL), dried overNa₂SO₄, and evaporated to dryness to yield a crude Compound 18B (46 g,yield 100%), which was used for the next step without furtherpurification.

A solution of polyphosphoric acid (75 g) in toluene was stirred to 90°C., then to the solution was added Compound 18B (46 g) in toluene (20mL). The mixture was stirred at 90° C. for 4 h, then poured into ice,and stirred for 30 min. Cooling to rt, the mixture was extracted withethyl acetate (100 mL×2), washed with brine (100 mL), dried over Na₂SO₄,concentrated, and purified by silica gel column chromatography(petroleum ether, 100% v/v) to yield a mixture of Compound 18C andCompound 18C′ (7 g, yield 21%) as a white solid. ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 6.69 (d, J=1.6 Hz, 1H), 6.84 (d,J=1.6 Hz, 1H), 7.34 (s, 2H), 7.61 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.65(s, 1H).

To a solution of Compound 18C and 18C′ (8 g, 42.8 mmol) in THF (60 mL)was added n-BuLi (20 mL) at −78° C. under N₂. After stirred for 30 min,diethyl oxalate (6 g, 51 mmol) was added to the mixture and it wasstirred at −78° C. for 1 h, followed by the addition of aq sat. NH₄Cl.The resulting mixture was extracted with ethyl acetate (100 mL×2),washed with aq sat. NaHCO₃ (100 mL×2), brine (100 mL), dried overNa₂SO₄, concentrated, and purified by silica gel column chromatography(ethyl acetate in petroleum ether, 20% v/v) to give Compound 18D (2.5 g,yield 19%) and Compound 18D′ (250 mg, yield 1.9%) as a yellow solid.Compound 18D: LC-MS (m/z): 287 [M1]⁻; ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.45 (t, J=6.8 Hz, 3H), 4.45 (q, J=6.8 Hz,2H), 6.79 (d, J=2.4 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.83 (s, 1H).Compound 18D′: LC-MS (m/z): 287 [M+1]⁻; ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.47 (t, J=6.8 Hz, 3H), 4.50 (q, J=8.8 Hz,2H), 7.47 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 8.12 (s, 1H).

To a solution of Compound 18D (750 mg, 2.6 mmol) in DCM (50 mL) wasadded DAST (2.5 g, 15.7 mmol) at 0° C. and the mixture was stirred at rtovernight. It was poured into ice-water, followed by addition of aq sat.aq NaHCO₃ (20 mL). The resulted mixture was extracted with DCM (50mL×2), washed with brine (50 mL), dried over Na₂SO₄, and concentrated.The crude product was purified by silica gel column chromatography(ethyl acetate in petroleum ether, 10% v/v) to render Compound 18E (350mg, yield 51%) as a yellow liquid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.26 (t, J=6.8 Hz, 3H), 4.31 (q, J=6.8 Hz,2H), 6.71 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.76 (s, 1H).

To a solution of Compound 18E (150 mg, 0.5 mmol) in THF (20 mL) wasadded LiOH (24 mg, 0.6 mmol) in water (5 mL) and the mixture was stirredat rt 3 h. It was concentrated by removal of EtOH and adjusted to pH 7with diluted HCl. Lyophilization of the solution led to Compound 18F(124 mg, crude), which was used for the next step without furtherpurification. LC-MS (m/z): 280 [M−1]⁻; ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 7.17 (s, 1H), 8.24 (s, 1H), 8.26 (s, 1H).

A mixture of Compound 18F (124 mg, 0.44 mmol), EDCI (117 mg, 0.61 mmol),HOBt (83 mg, 0.61 mmol), Intermediate A (115 mg, 0.41 mmol) in DCM (20mL) was stirred at rt overnight. To the mixture was added dropwise aqsat. NaHCO₃. It was then extracted with DCM (50 mL×2), washed with brine(50 mL), dried over Na₂SO₄, and concentrated. The crude product waspurified by prep-HPLC to give Compound 18 (78 mg, yield 26%) as a whitesolid. LC-MS (m/z): 541 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.13 (s, 4H), 2.89 (m, 2H), 3.09 (brs,1H), 3.37 (brs, 1H), 3.62 (brs, 1H), 3.87 (brs, 2H), 4.25 (s, 4H), 4.36(m, 1H), 5.21 (s, 1H), 6.75 (s, 1H), 6.83 (s, 2H), 6.89 (s, 1H), 7.62(d, J=2 Hz, 1H), 7.68 (d, J=2 Hz, 1H), 7.80 (s, 1H), 11.41 (s, 1H).

Example 19

To a solution of Compound 18D′ (240 mg, 0.84 mmol) in DCM (11 mL) wasadded DAST (740 mg, 4.59 mmol) at 0° C. and the mixture was stirred atrt overnight. The reaction was quenched by pouring the mixture intoice-water, and followed with addition of sat. aq NaHCO₃ (20 mL). It wasextracted with DCM (50 mL×2), washed with brine (50 mL×1), dried overNa₂SO₄, and concentrated. The crude product was purified by silica gelcolumn chromatography (ethyl acetate in petroleum ether, 10% v/v) torender Compound 19A (245 mg, yield 94.8%) as a yellow liquid. ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.35-1.40 (m, 3H),4.35-4.44 (m, 2H), 7.23 (s, 1H), 7.40-7.42 (d, J=8.8 Hz, 1H), 7.46-7.48(d, J=8.8 Hz, 1H).

To a solution of Compound 19A (245 mg, 0.795 mmol) in THF (10 mL) wasadded LiOH (63 mg, 1.49 mmol) in water (5 mL) and the mixture wasstirred at rt for 4 h. The mixture was concentrated by removal ofsolvent and then adjusted pH to 6 with diluted HCl. Lyophilization ofthe solution gave rise to Compound 19B (210 mg, crude), which was usedfor the next step without further purification. LC-MS (m/z): 279 [M−1]⁻.

A mixture of Compound 19B (135 mg, 0.48 mmol), EDCI (135 mg, 0.70 mmol),HOBt (94 mg, 0.69 mmol), Intermediate A (130 mg, 0.47 mmol) in DCM (20mL) was stirred at rt overnight. The mixture was diluted with aq sat.NaHCO₃, extracted with DCM (50 mL×2), washed with brine (50 mL×1), driedover Na₂SO₄, and concentrated. The crude product was purified byprep-HPLC to give 19 (83 mg, yield 32%) as a white solid. LC-MS (m/z):541.2 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.11 (s, 4H), 2.91-2.99 (m, 2H), 3.41-3.42 (m, 1H), 3.56-3.62 (m,1H), 3.78 (s, 1H), 3.94-3.80 (m, 2H), 4.11-4.15 (m, 4H) 4.48 (s, 1H),5.03 (s, 1H), 6.69-6.77 (m, 2H), 6.80 (s, 1H), 7.35-7.38 (d, J=9.2 Hz,1H), 7.44-7.46 (d, J=8.8 Hz, 1H), 8.02-8.04 (d, J=8.8 Hz, 1H), 11.70 (s,1H).

Example 20

To a solution of Compound 20A (2.2 g, 12 mmol) in anhydroustetrahydrofuran (80 mL) was added zinc (1.01 g, 15.6 mmol). The mixturewas heated at 75° C. under N₂ atmosphere and ethyl 2-bromo-2,2-difluoroacetate (1.9 mL, 15 mmol) was slowly added. The mixture washeated under the same conditions for 2 h. After cooling, it wasfiltered. The filtrate was concentrated to give a crude product, whichwas purified by silica gel column chromatography (ethyl acetate inpetroleum ether, 20% v/v) to afford Compound 20B (1.9 g, yield 58%) as acolorless oil. LCMS (m/z): 309 [M+1]⁺.

To a solution of Compound 20B (500 mg, 1.63 mmol) in DCM (20 mL) wasadded dropwise N,N′-thiocarbonyldiimidazole (349 mg, 1.95 mmol) in DCM(10 mL) at 72° C. After 3 h, the reaction mixture was cooled to rt andconcentrated in vacuum to give a crude product. It was purified bysilica gel column chromatography (ethyl acetate in petroleum ether, 20%v/v) to render Compound 20C (590 mg, yield 87%) as a colorless oil. LCMS(m/z): 418 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.26 (t, J=6.8 Hz, 3H), 4.31 (q, J=6.8 Hz, 2H), 6.92 (m, 1H), 7.09(s, 1H), 7.28 (m, 1H), 7.60 (m, 2H), 7.70-7.81 (m, 3H), 8.07 (d, J=7.2Hz, 1H), 8.13 (s, 1H), 8.41 (s, 1H), 8.70 (d, J=4.4 Hz, 1H).

To a solution of n-Bu₃SnH (821 mg, 2.8 mmol) and AIBN (2 mg, cat.) inrefluxing toluene (10 ml) was added dropwise the Compound 20C (590 mg,1.4 mmol) in toluene (10 ml). After stirred for 3 h at 110° C., thereaction mixture was cooled to rt and concentrated in vacuum to purifiedby silica gel column chromatography (ethyl acetate in petroleum ether,20% v/v) to afford Compound 20D (200 mg, yield 50%) as a colorless oil.LCMS (m/z): 392 [M+1]⁺.

To a solution of Compound 20D (100 mg, 0.34 mmol) in THF/MeOH/water (3mL, 1:1:1, v/v) was added LiOH.H₂O (36 mg, 1.5 mmol). The mixture wasstirred at 25° C. for 1 h. After the completion of the reaction, water(20 mL) was added. It was extracted with ethyl acetate (20 mL×2). Theaqueous phrase was adjusted pH to 6 with 1 N HCl and extracted withethyl acetate (20 mL×2). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuum to give crude productCompound 20E (90 mg, crude) as a yellow solid. LCMS (m/z): 264 [M+1]⁺.

To a mixture of Compound 20E (80 mg, 0.3 mmol) in DCM (10 mL) was addedEDCI (88 mg, 0.45 mmol), HOBt (62 mg, 0.45 mmol) and Intermediate A (85mg, 0.3 mmol) and stirred at 25° C. overnight. After the addition ofwater (10 mL), the mixture was extracted with DCM (20 mL×3), dried overanhydrous Na₂SO₄, purified by prep-HPLC to render Compound 20 (35 mg,yield 22%) as a white solid. LCMS (m/z): 524 [M+1]⁺; ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 1.99 (s, 4H), 2.72 (m, 2H),3.19 (s, 1H), 3.42-3.66 (m, 6H), 4.20 (s, 4H), 4.40 (s, 1H), 4.77 (s,1H), 4.89 (s, 1H), 6.68 (m, 1H), 6.76 (m, 2H), 7.45-7.54 (m, 2H), 7.70(m, 1H), 7.77-7.85 (m, 3H), 7.99 (d, J=8.0 Hz, 1H), 8.28 (t, J=7.6 Hz,1H), 8.90 (s, 1H), 11.43 (s, 1H).

Example 21

To a solution of Compound 21A (2.5 g, 20 mmol) in CCl₄ (100 mL) wasadded NBS (7.12 g, 40 mmol), BPO (100 mg) and it was stirred at refluxovernight. The mixture was purified by column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to render Compound 21B(2.34 g, yield 41%) as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 4.60 (s, 2H), 4.62 (s, 2H), 6.98 (m, 1H),7.08 (m, 1H), 7.33 (m, 1H).

To a solution of diethyl malonate (1.52 mL, 10 mmol) in THF (100 mL) wasadded NaH (60%, 400 mg, 10 mmol) at 0° C. and stirred at 0° C. for 15min. To the mixture was added Compound 21B (2.8 g, 10 mmol) at 0° C. andstirred for 15 min and then followed by addition of NaH (60%, 400 mg, 10mmol) at 0° C. The mixture was stirred at rt for 2 h and was filtered toremove the salt. The filtrate was concentrated and purified by flashcolumn (ethyl acetate in petroleum ether, 10% v/v) to give Compound 21C(2.2 g, yield 79%) as a colorless oil. LC-MS (m/z): 281 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.26 (t, J=7.0 Hz,6H), 3.53 (s, 2H), 3.56 (s, 2H), 4.20 (m, 4H), 6.87 (m, 2H), 7.12 (m,1H).

To a solution of Compound 21B (2.2 g, 7.9 mmol) in ethanol (30 mL) wasadded a solution of LiOH (1.26 g, 31.4 mmol) in water (30 mL) andstirred at rt overnight. The mixture was concentrated to remove ethanol,acidified with conc. aqueous HCl solution, extracted with ethyl acetate(100 mL×3) and concentrated to render Compound 21D (1 g, yield 62%) as ayellow solid. LC-MS (m/z): 247 [M+23]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.38 (s, 2H), 3.42 (s, 2H), 6.93 (m, 1H),7.05 (m, 1H), 7.21 (m, 1H), 12.93 (s, 2H).

To a solution of Compound 21D (1 g, 4.5 mmol) in DMSO (15 mL) was addedNaCl (1 g). The mixture was stirred at 130° C. for 6 h. After theaddition of ethyl acetate (100 mL), the mixture was washed with water(200 mL×3) and brine (200 mL×1), dried over anhydrous Na₂SO₄, andconcentrated to yield Compound 21E (0.6 g, yield 74%) as a brown solid.¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 3.08 (m,4H), 3.29 (m, 1H), 6.92 (m, 1H), 7.03 (m, 1H), 7.21 (m, 1H), 12.37 (s,1H).

To a solution of Compound 21E (0.6 g, 3.3 mmol) in DCM (10 mL) was addedB₂H₆ in THF solution (1M, 4 mL, 4 mmol) at −78° C. under N₂ and stirredat rt for 1 h. MeOH (2 mL) was added to the mixture and it was stirredat the same temperature overnight. After removal of the solvents, theresidues were purified with flash column chromatography (ethyl acetatein petroleum ether, 35% v/v) to give Compound 21F (250 mg, yield 46%) asa yellow oil. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.70 (m, 3H), 3.04 (m, 2H), 3.65 (d, J=6.4 Hz, 2H), 6.80 (m, 1H),6.87 (m, 1H), 7.11 (m, 1H).

To a solution of Compound 21F (6.3 g, 38 mmol) in DCM (300 mL) was addedDMP (19 g, 45.5 mmol) at 0° C. and it was stirred at rt for 3 h. Themixture was concentrated and purified by flash column chromatography(ethyl acetate in petroleum ether, 20% v/v) to give Compound 21G (6 g,yield 96%) as a yellow oil. ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 3.23 (m, 5H), 6.88 (m, 2H), 7.15 (m, 1H), 9.77 (d, J=0.8Hz, 1H).

To a solution of Na₂S₂O₅ (3.6 g, 73.2 mmol) in water (100 mL) was addedCompound 21G (6 g, 36.6 mmol) and it was stirred at rt for 2 h andfollowed by the addition of NaCN (3.6 g, 73.2 mmol). The mixture wasstirred at rt overnight. It was extracted with ethyl acetate (100 mL×3),dried over anhydrous Na₂SO₄, purified by flash column chromatography(ethyl acetate in petroleum, 30% v/v) to give Compound 21H (3.3 g, 47%)as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks:δ (ppm) 2.96 (m, 3H), 3.16 (m, 2H), 4.45 (m, 1H), 6.86 (m, 2H), 7.14 (m,1H).

To a solution of Compound 21H (3.3 g, 17.3 mmol) in MeOH (100 mL) wasbubbled with a gentle stream of HCl gas (dried over cone. H₂SO₄) for 6 hand was allowed to stand overnight at 4° C. To the mixture was addedwater (50 mL) and it was stirred at rt for 3 h. Saturated aqueous NaHCO₃solution was added to adjust pH >7, the mixture was then extracted withethyl acetate (100 mL×3), washed with brine (100 mL×1), dried overanhydrous Na₂SO₄, and purified by flash column chromatography (ethylacetate in petroleum ether, 25% v/v) to give Compound 21I (1.9 g, yield49%) as a yellow oil. ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 2.90 (m, 5H), 3.77 (d, J=2.4 Hz, 3H), 4.27 (d, J=3.6 Hz,1H), 6.81 (m, 2H), 7.07 (m, 1H).

To a solution of Compound 21I (1.9 g, 8.5 mmol) in DCM (100 mL) wasadded DMP (5.4 g, 12.7 mmol) at 0° C. and it was stirred at rt for 3 h.After removal of the solvent, the residues were purified by flash columnchromatography (ethyl acetate in petroleum ether, 10% v/v) to giveCompound 21J (1.7 g, yield 90%) as a colorless oil. ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 3.19 (m, 4H), 3.91 (s, 3H),4.07 (m, 1H), 6.83 (m, 2H), 7.10 (m, 1H).

To a solution of Compound 21J (444 mg, 2 mmol) in DCM (10 mL) was addedDAST (1 mL, 8 mmol) and it was stirred at 25° C. overnight. The mixturewas purified by flash column chromatography (ethyl acetate in petroleumether, 2% v/v) to give 21K (300 mg, 61%) as a yellow oil. LC-MS (m/z):225 [M−19]⁺.

To a solution of Compound 21K (300 mg, 1.23 mmol) in MeOH (5 mL) wasadded a solution of LiOH (100 mg, 2.46 mmol) in water (5 mL) and it wasstirred at rt overnight. The mixture was acidified using 1M aqueous HClsolution, extracted with ethyl acetate (10 mL×3), dried over anhydrousNa₂SO₄, and concentrated to give Compound 21L (200 mg, yield 35%) as acolorless oil. LC-MS (m/z): 229 [M−1]⁻.

To a solution of Compound 21L (230 mg, 0.87 mmol) in DCM (10 mL) wasadded EDCI (250 mg, 1.3 mmol), HOBt (175 mg, 1.3 mmol), Intermediate A(240 mg, 0.87 mmol) and it was stirred at rt overnight. The mixture wasdiluted with DCM (20 mL), washed with water (50 mL×2) and brine (50mL×1), dried over anhydrous Na₂SO₄, concentrated, and purified byprep-HPLC to give Compound 21 (20 mg, yield 5%) as a white solid. LC-MS(m/z): 491 [M+1]; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.15 (br, 4H), 2.61 (m, 2H), 2.91 (m, 5H), 3.38 (br, 1H), 3.54(br, 1H), 3.88 (s, 2H), 4.20 (m, 4H), 4.44 (s, 1H), 5.20 (s, 1H), 6.83(m, 4H), 6.90 (m, 1H), 7.05 (m, 1H), 7.39 (m, 1H), 11.42 (s, 1H).

Example 22

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (7.2 g, 32 mmol) inTHF (150 mL) was added NaH (1.3 g, 32 mmol) at 0° C. under N₂ and it wasstirred at this temperature for 30 min, followed by the addition ofCompound 22A (5 g, 32 mmol) in THF (15 mL). Stirred at 40° C. for 1 h,the mixture was first cooled down to rt, and then added water, extractedwith ethyl acetate (50 mL×2), washed with brine (50 mL×1), dried overNa₂SO₄, concentrated, and purified by silica gel column chromatography(ethyl acetate in petroleum ether, 20% v/v) to give Compound 22B (7 g,yield 97%). LC-MS (m/z): 227 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.36 (t, J=6.8 Hz, 3H), 4.28 (q, J=7.2 Hz,2H), 6.54 (d, J=16 Hz, 1H), 7.5 (m, 2H), 7.65 (d, J=10 Hz, 1H), 7.82 (m,4H), 7.91 (s, 1H).

To a solution of Compound 22B (7 g, 31 mmol) in methanol (50 mL) and THF(30 mL) was added Pd/C (700 mg) and it was stirred at 25° C. for 4 hunder H₂. The mixture was filtered, and the filtrate was concentrated torender Compound 22C (7 g, crude), which was used for the next stepwithout further purification. LC-MS (m/z): 229 [M+1]⁺.

To a solution of AlLiH₄ (1.16 g, 31 mmol) in THF (100 mL) was addedCompound 22C (7 g, 31 mmol) in THF (20 mL) at −60° C. under N₂ and themixture was stirred for 2 h, and then allowed the temperature raised tort. Sodium sulfate was added to the mixture. After filtration, thefiltrate was purified by silica gel column chromatography (ethyl acetatein petroleum ether, 20% v/v) to yield the Compound 22D (5.6 g, yield98%) as a white solid. LC-MS (m/z): 169 [M−18]⁺; ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 1.06 (s, 1H), 1.97 (m, 2H), 2.87 (d,J=7.6 Hz, 2H), 3.70 (d, J=6.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.43 (m,2H), 7.63 (s, 1H), 7.78 (m, 3H).

To a solution of Compound 22D (3 g, 16 mmol) in DCM (100 mL) was addedDMP (8.2 g, 19 mmol) and the mixture was stirred at rt for 2 h, and thenfiltered. The filtrate was washed with aq sat. NaHCO₃ (2×50 mL),extracted with DCM (2×50 mL), washed with brine (1×50 mL), dried overNa₂SO₄, concentrated, and purified by silica gel column chromatography(ethyl acetate in petroleum ether, 20% v/v) to afford Compound 22E (2.6g, yield 88%) as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.87 (d, J=7.2 Hz, 2H), 3.12 (d, J=7.6 Hz,2H), 7.33 (d, J=8.4 Hz, 1H), 7.44 (m, 2H), 7.63 (s, 1H), 7.79 (m, 3H),9.86 (s, 1H).

Compound 22E (2.6 g, 14 mmol) was added to a solution of sodiummetabisulfate (2.7 g, 14 mmol) in water (100 mL). The mixture wasvigorously stirred for 2 h at rt, and after the addition of NaCN (1.4mg, 28 mmol) it was stirred overnight. The mixture was added water (30mL) and THF (10 mL), extracted with ethyl acetate (100 mL×2), washedwith brine (100 mL×1), dried over Na₂SO₄, concentrated to yield Compound22F (2 g, 66% yield). LC-MS (m/z): 212 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400MHz)□□ major characteristic peaks: δ (ppm) 2.25 (m, 2H), 2.99 (m, 2H),4.43 (t, J=6.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.44 (m, 2H), 7.65 (s,1H), 7.81 (m, 3H).

To a solution of Compound 22F (2.0 g, 9.5 mmol) in EtOH (30 mL) at 0° C.was bubbled with a gentle stream of HCl (gas) (dried over con. H₂SO₄)for 5 h. The mixture was added water (20 mL), stirred at rt for 2 h, andadjusted pH to 7 with diluted NaOH (2 M). It was extracted with DCM (100mL×2), washed with brine (50 mL×1), dried over Na₂SO₄, concentrated, andpurified by silica gel column chromatography (ethyl acetate in petroleumether, 33% v/v) to render Compound 22G (1.56 g, yield 64%) as a yellowoil. LC-MS (m/z): 259 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.27 (t, J=7.6 Hz, 1H), 2.03 (m, 1H), 2.22(m, 1H), 2.92 (m, 2H), 4.20 (m, 3H), 7.35 (d, J=9.2 Hz, 1H), 7.44 (m,2H), 7.65 (s, 1H), 7.79 (m, 3H).

To a solution of Compound 22G (500 mg, 1.94 mmol) in DCM (20 mL) wasadded DMP (986 mg, 2.3 mmol) and the mixture was stirred at rt for 2 hand then filtered. The filtrate was washed with aq sat. NaHCO₃ (50 mL×2)and aq sat. Na₂S₂O₃ (50 mL×2), extracted with DCM (50 mL×2), washed withbrine (50 mL×1), dried over Na₂SO₄, and concentrated to yield Compound22H (450 mg, yield 91%) as a yellow oil. LC-MS (m/z): 239 [M−18]⁺.

To a solution of Compound 22H (450 mg, 1.76 mmol) in DCM (20 mL) wasadded DAST (1.4 g, 8.8 mmol) at 0° C. and the mixture was stirred at rtovernight. The reaction mixture was poured into ice-water, extractedwith DCM (50 mL×2), washed with brine (50 mL×1), dried over Na₂SO₄, andconcentrated. The crude product was purified by silica gel columnchromatography (ethyl acetate in petroleum ether, 20% v/v) to yieldCompound 221 (450 mg, yield 92%) as a colorless oil. LC-MS (m/z): 279[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.31(t, J=7.2 Hz, 1H), 2.47 (m, 2H), 2.98 (m, 2H), 4.27 (q, J=7.2 Hz, 2H),7.31 (d, J=8.4 Hz, 1H), 7.45 (m, 2H), 7.63 (s, 1H), 7.77 (m, 3H).

To a solution of Compound 221 (450 mg, 1.6 mmol) in EtOH (5 mL) wasadded LiOH (136 mg, 3.2 mmol) in water (5 mL) and the mixture wasstirred at rt overnight. After concentration by evaporation, the mixturewas adjusted to pH 2 with diluted HCl, extracted with DCM (20 mL×2),washed with brine (20 mL×1), dried over Na₂SO₄, and concentrated to giveCompound 22J (250 mg, yield 62%), which was used for the next stepwithout further purification. LC-MS (m/z): 251 [M+1]⁺.

A mixture of Compound 22J (100 mg, 0.4 mmol), EDCI (115 mg, 0.6 mmol),HOBt (82 mg, 0.6 mmol), Intermediate A (110 mg, 0.4 mmol) in DCM (20 mL)was stirred at rt overnight. The reaction mixture was diluted withwater, extracted with DCM (50 mL×2), washed with brine (50 mL×1), driedover Na₂SO₄, and concentrated. The crude product was purified first byprep-HPLC, followed by chiral-prep-HPLC to give Compound 22K (24 mg,yield 12%) as a white solid and Compound 22 (22 mg, yield 11%) as awhite solid. For Compound 22K: LC-MS (m/z): 511 [M+1]⁺; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 1.81 (s, 4H), 2.46 (m, 3H),2.70 (m, 5H), 2.98 (d, J=3.6 Hz, 2H), 3.94 (m, 4H), 4.20 (s, 1H), 5.07(s, 1H), 6.82 (m, 4H), 7.22 (m, 1H), 7.45 (m, 2H), 7.54 (s, 1H), 7.77(m, 3H). For Compound 22: LC-MS (m/z): 511 [M+1]⁺; ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 1.89 (s, 4H), 2.36 (m, 2H),2.88 (m, 4H), 2.99 (m, 3H), 3.19 (s, 1H), 4.04 (m, 4H), 4.25 (s, 1H),4.77 (d, J=5.6 Hz, 1H), 6.86 (m, 3H), 7.28 (m, 1H), 7.44 (m, 2H), 7.59(s, 1H), 7.78 (m, 3H).

Example 23

To a solution of Compound 23A (2.36 g, 20.0 mmol) in tetrahydrofuran (30mL) stirring at −70° C. (CO₂, acetone bath) was added n-BuLi (8.0 mL,20.0 mmol, 1.6 M in hexanes). The reaction was stirred for 30 min(yellow color) and added dropwise via a cannulated needle into asolution of diethyl oxalate (2.92 g, 20.0 mmol) in tetrahydrofuran (20mL) stirring at −70° C. The reaction mixture was stirred for 1 h andthen quenched with saturated aqueous ammonium chloride solution. Themixture was warmed to rt, diluted with dichloromethane, and washed with0.1 N HCl. The organic layer was separated, dried over anhydrousmagnesium sulfate, filtered, and evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel (ethyl acetate inpetroleum ether, 10% v/v) to provide Compound 23B (1.10 g, yield 25%).¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.46 (t,J=7.2 Hz, 3H), 4.87 (q, J=7.2 Hz, 2H), 7.35-7.37 (m, 1H), 7.55-7.57 (m,1H), 7.61-7.64 (m, 1H), 7.77-7.78 (m, 1H), 8.09-8.10 (m, 1H).

To a solution of Compound 23B (800 mg, 3.67 mmol) in CH₂Cl₂ (10 mL) wasadded DAST (1.77 g, 11.01 mmol). The reaction mixture was stirred for 10h and then poured into ice-water, extracted with CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄, filtered, evaporated to givedesired product Compound 23C (860 mg, yield 97%). ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 1.35-1.40 (m, 3H), 4.33-4.43(m, 2H), 7.14-7.15 (m, 1H), 7.31-7.33 (m, 1H), 7.38-7.42 (m, 1H),7.54-7.56 (m, 1H), 7.64-7.66 (m, 1H).

To a solution of Compound 23C (480 mg, 2 mmol) in THF (2 mL) was addedLiOH.H₂O (3 mmol, 126 mg), H₂O (2 mL) and MeOH (2 mL). The reactionmixture was stirred for 3 h at 25° C., neutralized with 1 N HCl, andevaporated to dryness. The residue was dissolved in H₂O and extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, filtered,evaporated to give Compound 23D (290 mg, yield 68%). LCMS (m/z): 213[M+1]⁺.

To a solution of Compound 23D (88 mg, 0.41 mmol) in DCM (10 mL) wasadded Intermediate A (114 mg, 0.41 mmol), HOBt (82 mg, 0.61 mmol) andEDCI (116 mg, 0.61 mmol). The mixture was stirred for 3 h at 25° C.,washed with brine, dried over Na₂SO₄, filtered, evaporated, and purifiedby prep-HPLC to give Compound 23 (30 mg, yield 15%) as a white solid.LC-MS (m/z): 473 [M+1]⁺; ¹H-NMR (MeOD-d₄, 400 MHz) major characteristicpeaks: δ (ppm) 1.77-1.78 (m, 4H), 2.55-2.64 (m, 4H), 2.74-2.75 (m, 2H),4.08-4.14 (m, 4H), 4.35-4.36 (m, 1H), 4.79 (d, J=4.0 Hz, 1H), 6.66-6.68(m, 1H), 6.76-6.78 (m, 1H), 6.83-6.84 (m, 1H), 7.00 (s, 1H), 7.30-7.34(m, 1H), 7.41-7.45 (m, 1H), 7.55-7.57 (m, 1H), 7.66-7.68 (m, 1H),7.81-7.83 (m, 1H).

Example 24

A mixture of Compound 24A (10 g, 89 mmol), 2-bromo-1,1-dimethoxyethane(15 g, 89 mmol), K₂CO₃ (18.4 g, 134 mmol), KI (100 mg) in DMF (100 mL)was stirred at reflux for 3 h, then cooled to rt, and filtered. Thefiltrate was added water (200 mL), extracted with ethyl acetate (100mL×2), washed with water (100 mL×3), brine (100 mL×1), dried overNa₂SO₄, concentrated, and purified by silica gel column chromatography(ethyl acetate in petroleum ether, 10% v/v) to render Compound 24B (15g, yield 85%) as a colorless liquid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.46 (s, 6H), 3.96 (d, J=5.2 Hz, 2H), 4.71(t, J=5.6 Hz, 1H), 6.90 (m, 2H), 7.26 (m, 2H).

A solution of polyphosphoric acid (90 g) in toluene was stirred to 90°C., then to the solution was added Compound 24B (15 g, 75 mmol) intoluene (20 mL) and the mixture was stirred at 90° C. for 3 h, thenpoured into ice, and stirred for 30 min. It was extracted with ethylacetate (100 mL×2), washed with brine (100 mL×1), dried over Na₂SO₄,concentrated, and purified by column chromatography on silica gel(petroleum ether, 100% v/v) to yield Compound 24C (4.5 g, yield 44%) asa red liquid. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 6.742-6.746 (m, 1H), 6.994-7.035 (m, 1H), 7.24-7.26 (m, 1H),7.41-7.44 (m, 1H), 7.651-7.655 (d, J=1.6 Hz, 1H).

To a solution of Compound 24C (4.5 g, 33 mmol) in THF (20 mL) was addedn-BuLi (15 mL) at −78° C. under N₂ and the mixture was stirred for 30min, before the addition of diethyl oxalate (10.8 g, 74 mmol). Themixture was stirred at −78° C. for 1 h, and quenched with addition of aqsat. NH₄Cl. It was extracted with ethyl acetate (2×50 mL), washed withsat. NaHCO₃ (50 mL×2), brine (50 mL), dried over Na₂SO₄, concentrated,and purified by column chromatography on silica gel (ethyl acetate inpetroleum ether, 20% v/v) to give Compound 24D (2.5 g, yield 32%) as ayellow solid.

To a solution of Compound 24D (1 g, 4.2 mmol) in DCM (50 mL) was addedDAST (3.18 g, 18 mmol) at 0° C. and the mixture was stirred at rtovernight, poured into ice-water, and added sat. aq NaHCO₃ (20 mL). Themixture was extracted with DCM (50 mL×2), washed with brine (50 mL×1),dried over Na₂SO₄, and concentrated. The crude product was purified bysilica gel column chromatography (ethyl acetate in petroleum ether, 10%v/v) to yield Compound 24E (600 mg, yield 55%) as a yellow liquid.

To a solution of Compound 24E (120 mg, 0.46 mmol) in EtOH (5 mL) wasadded LiOH (46 mg, 1.09 mmol) in water (5 mL) and the mixture wasstirred at rt overnight, concentrated to remove EtOH, and adjusted to pH7 with diluted HCl. Lyophilization of the solution provided Compound 24F(60 mg, crude), which was used for the next step without furtherpurification. LC-MS (m/z): 229 [M−1]⁻.

A mixture of Compound 24F (60 mg, 0.26 mmol), EDCI (75 mg, 0.39 mmol),HOBt (53 mg, 0.39 mmol), Intermediate A (72 mg, 0.41 mmol) in DCM (10mL) was stirred at rt overnight. After quenched with sat. NaHCO₃, themixture was extracted with DCM (2×50 mL), washed with brine (1×50 mL),dried over Na₂SO₄, concentrated. The crude product was purified byprep-HPLC to give Compound 24 (2 mg, yield 2%) as a white solid. LC-MS(m/z): 491 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.85 (m, 4H), 3.07 (m, 2H), 3.43 (m, 4H), 4.15 (s, 4H), 4.45 (s,1H), 4.70 (s, 1H), 5.90 (s, 1H), 6.67 (m, 2H), 6.79 (s, 1H), 7.02 (s,1H), 7.36 (s, 1H), 7.56 (s, 1H), 7.73 (s, 1H), 8.85 (s, 1H), 9.49 (s,1H).

Example 25

Compound 25A (5.64 g, 40 mmol) and 2-oxopropanoic acid (3.52 g, 40 mmol)were dissolved in MeOH (4 mL). To this solution, KOH (3.95 g, 60 mmol)in MeOH (10 mL) was added. The mixture was stirred at rt for 5 h. Theprecipitate was isolated by filtration. Compound 25B (8.5 g, yield 85%)was obtained as a yellow solid. LCMS (m/z): 211 [M+1]⁺.

Acetyl chloride (3.84 mL) was added dropwise to MeOH (23 mL) at 0° C.Then Compound 25B (3.98 mg, 16 mmol) was added to the mixture. Themixture was heated to reflux overnight. After evaporation, the mixturewas diluted with water, extracted by ethyl acetate and dried overanhydrous Na₂SO₄. After evaporation to dryness, the residue wasrecrystallized from EtOH. Compound 25C (1.34 g, yield 37%) was obtainedas a yellow solid. LCMS (m/z): 247 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.94 (s, 3H), 7.36 (d, J=16 Hz, 1H), 7.40(d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.82 (d, J=16.4 Hz, 1H).

To the solution of Compound 25C (225 mg, 1 mmol) in CH₂Cl₂ (5 mL) wasadded DAST (483.6 mg, 3 mmol) at 0° C. The mixture was stirred at rtovernight. After evaporation, the residue was purified by silica gelcolumn chromatography (ethyl acetate in petroleum, 5% v/v). Compound 25Dwas obtained as a yellow solid (150 mg, 60%). LCMS (m/z): 227 [M−19]⁺.

To the solution of compound 25D (86 mg, 0.35 mmol) in MeOH (5 mL) andH₂O (1.5 mL) was added LiOH.H₂O (74 mg, 1.75 mmol) at 0° C. The mixturewas stirred for an hour at rt. After evaporation of the solvent, theresidue was diluted with water and the mixture was adjusted to pH 4 with1 M HCl. The resulted mixture was extracted with ethyl acetate and driedover anhydrous Na₂SO₄. After evaporation, Compound 25E was obtained as ayellow solid (63 mg, yield 77%). LCMS (m/z): 231 [M−1]⁻; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 6.27-6.31 (m, 1H), 7.08 (d,J=16.4 Hz, 1H), 7.34-7.40 (m, 4H).

To the solution of Compound 25E (63 mg, 0.27 mmol), Intermediate A (75mg, 0.27 mmol) in DCM (4 mL) was added EDCI (52 mg, 0.27 mmol). Themixture was stirred at rt overnight. After evaporation, the crude waspurified by prep-HPLC to give Compound 25 (11 mg, yield 6.7%) as a whitesolid. LCMS (m/z): 493 [M+1]⁻; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.02 (m, 4H), 2.71-2.85 (m, 2H), 3.09 (m,2H), 3.60-3.89 (m, 3H), 4.15 (s, 4H), 4.34 (s, 1H), 4.91 (s, 1H),6.19-6.23 (m, 1H), 6.78-7.00 (m, 4H), 7.30-7.35 (m, 4H), 8.72 (s, 1H),11.7 (s, 1H).

Example 26

A solution of Compound 11E (100 mg, 0.41 mmol), Intermediate C (222 mg,0.41 mmol), EDCI (118 mg, 0.62 mmol) and HOBt (84 mg, 0.62 mmol) in DCM(20 mL) was stirred at rt overnight. The mixture was diluted with ethylacetate (150 mL), washed with water and brine, dried over anhydrousNa₂SO₄, and evaporated to render Compound 26A (200 mg, yield 63%) as ayellow oil, which was used for next step directly. LCMS (m/z): 776[M+1]⁺.

A mixture of Compound 26A (200 mg, 0.23 mmol) and Bu₄NF (20 mg) in THF(10 mL) was stirred at 25° C. overnight. It was then diluted with ethylacetate (150 mL), washed with water and brine, dried with anhydrousNa₂SO₄, evaporated, and purified by prep-HPLC to yield Compound 26B (103mg, yield 68%) as colorless oil. LCMS (m/z): 662 [M+1]⁺.

A solution of Compound 26B (103 mg, 0.16 mmol) and TFA (0.5 mL) in DCM(5 mL) was stirred at rt for 2 h. The reaction was quenched withsaturated aqueous NaHCO₃, diluted with ethyl acetate (150 mL), washedwith water and brine, dried with anhydrous Na₂SO₄, evaporated, andpurified by prep-HPLC to afford Compound 26 (30 mg, yield 33%) as awhite solid. LCMS (m/z): 562 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.92-2.16 (m, 7H), 3.26-3.60 (m, 6H),4.05-4.20 (m, 5H), 4.51 (s, 1H), 6.00-6.13 (m, 1H), 6.68-6.84 (m, 3H),7.51-7.54 (m, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.80 (d, J=17.6 Hz, 1H), 8.15(br s, 2H).

Example 27

To a solution of Compound 11C (564 mg, 2.24 mmol) in dichloromethane,under an atmosphere of nitrogen at 76° C. was added diisobutylaluminiumhydride (2.95 ml, 2.95 mmol). The solution was stirred at 76° C. for 45min, and then allowed to warm to rt. A mixture of water/methanol (10 mL,1/1 v/v) was added dropwise. The two layers were separated and theaqueous phase was extracted with dichloromethane. The combined organicextracts were dried, evaporated and purified on silica gel column (ethylacetate/PE) to give Compound 27A (153 mg, yield 27%) as a yellow solid.¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.25-1.29(m, 3H), 4.27-4.35 (m, 2H), 5.29 (s, 1H), 6.72 (s, 1H), 7.242-7.248 (d,J=2.4 Hz, 1H), 7.261-7.269 (d, J=3.2 Hz, 1H), 7.38-7.40 (d, J=8.4 Hz,1H). 7.534-7.538 (d, J=2.4 Hz, 1H).

To a solution of Compound 27A (184 mg, 0.72 mmol) in DCM (8 mL) wasadded DAST (380 mg, 2.36 mmol) at 0° C. and the mixture was stirred atrt overnight. It was poured into ice-water, extracted with DCM (2×50mL), washed with brine (1×50 mL), dried over Na₂SO₄, and concentrated.The crude product was purified by silica gel column chromatography(ethyl acetate in petroleum ether, 10% v/v) to afford Compound 27B (70mg, yield 37.9%) as a yellow liquid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.30-1.34 (m, 3H), 4.33-4.37 (m, 2H),5.85-5.97 (d, J=47.6 Hz, 1H), 6.89-6.90 (d, J=4.0 Hz, 1H), 7.30-7.33 (d,J=8.8 Hz, 1H), 7.43-7.45 (d, J=8.8 Hz, 1H), 7.583-7.588 (d, J=2.0 Hz,1H).

To a solution of Compound 27B (70 mg, 0.273 mmol) in THF (5 mL) wasadded LiOH (22 mg, 0.52 mmol) in water (2.5 mL) and the mixture wasstirred at rt for 4 h. It was concentrated and adjusted to pH 6 withdiluted HCl. Lyophilization of the solution led to Compound 27C (210 mg,crude), which was used for the next step without further purification.LC-MS (m/z): 227 [M−1]⁻.

A mixture of Compound 27C (66 mg, 0.29 mmol), EDCI (80.8 mg, 0.42 mmol),HOBt (56 mg, 0.42 mmol), Intermediate A (77.8 mg, 0.28 mmol) in DCM (12mL) was stirred at rt overnight. It was diluted with sat. aq NaHCO₃,extracted with DCM (2×50 mL), washed with brine (1×50 mL), dried overNa₂SO₄, and concentrated. The crude product was purified by prep-HPLC togive Compound 27 (15 mg, yield 10.6%) as a white solid. LC-MS (m/z):489.1 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.03-2.08 (m, 4H), 2.48 (s, 6H), 2.73-3.50 (m, 3H), 3.83-3.90 (m,2H), 4.16-4.22 (m, 3H), 4.45-4.64 (m, 1H), 4.88-5.08 (m, 1H), 5.72-5.96(m, 1H), 6.76-6.95 (m, 3H), 7.28-7.38 (m, 1H), 7.49-7.56 (m, 1H),7.75-8.70 (m, 1H), 11.11-11.80 (m, 1H).

Example 28

To 4-fluorothiophenol 28A (1.28 g, 10 mmol) in anhydrous acetone (40mL), under nitrogen at rt was added potassium carbonate (1.38 g, 10mmol). To the mixture was slowly added bromoacetaldehyde diethyl acetal(1.69 g, 10 mmol). The reaction mixture was stirred at rt overnight. Thepotassium carbonate was filtered off and washed thoroughly with acetone.The filtrate was then concentrated and the oily residue diluted with H₂Oand extracted with ethyl acetate. The ethyl acetate extracts were washedwith 0.5 M KOH, H₂O and brine, dried over anhydrous magnesium sulfate,filtered and concentrated. Purification by column chromatography onsilica gel (ethyl acetate in petroleum ether, 10% v/v) afforded Compound28B (1.54 g, yield 71%). ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 3.05 (d, J=6.4 Hz, 2H), 3.32 (s, 6H), 4.49 (t, J=6.4 Hz,1H), 6.97-7.01 (m, 2H), 7.38-7.42 (m, 2H).

To a 3-neck 100 mL flask was introduced polyphosphoric acid (5 g) andanhydrous chlorobenzene (30 ml). The mixture was stirred under nitrogenat reflux. Compound 28B (1.54 g, 7.1 mmol) was then added over 5 minperiod in 2 mL of chlorobenzene. Within 30 min the reaction mixtureturned relatively dark and it was kept under reflux for 3 h. The mixturewas cooled down to rt and the chlorobenzene layer decanted. The blacktar was suspended in H₂O (50 mL) and stirred for about 30 min. Theaqueous layer was extracted with CH₂Cl₂. The organic extracts werepooled with the chlorobenzene layer, treated with brine, dried overanhydrous magnesium sulfate, filtered and concentrated. Purification bycolumn chromatography on silica gel (petroleum ether, 100% v/v) affordedCompound 28C (470 mg, yield 43%). ¹H-NMR (MeOD-d₄, 400 MHz) majorcharacteristic peaks: δ (ppm) 7.11-7.16 (m, 1H), 7.34-7.35 (m, 1H),7.53-7.56 (m, 1H), 7.66-7.67 (m, 1H), 7.86-7.89 (m, 1H).

Compound 28C (470 mg, 3.1 mmol) was added to THF (10 mL) followed byaddition of n-BuLi (1.24 mL, 3.1 mmol) at rt. The reaction mixture wasstirred at rt for 60 min. Diethyl oxalate (905 mg, 6.2 mmol) was addedto THF (30 mL) −78° C. To this solution, 5-fluorobenzo[b]thiophene anionsolution was added dropwise and the reaction was stirred at −78° C. for20 min. It was quenched with saturated aqueous NH₄Cl (30 mL) andextracted with ethyl acetate (30 mL×3). The organic extracts wereconcentrated in vacuum and purified by column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to give the Compound 28D(450 mg, yield 57%) as an orange oil. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.36 (t, J=7.2 Hz, 3H), 4.36 (q, J=7.2 Hz,2H), 7.25-7.30 (m, 1H), 7.65-7.68 (m, 1H), 7.87-7.91 (m, 1H), 7.77-7.78(m, 1H), 8.35 (s, 1H).

To a solution of Compound 28D (450 mg, 1.78 mmol) in CH₂Cl₂ (10 mL) wasadded DAST (2.86 g, 17.8 mmol). The reaction mixture was stirred for 10h before poured into ice-water and extracted with CH₂Cl₂ (50 mL×2). Thecombined organic layers were dried over Na₂SO₄, filtered, and evaporatedto give Compound 28E (88 mg, yield 18%). ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.34 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz,2H), 7.26-7.31 (m, 1H), 7.64-7.67 (m, 1H), 7.72 (s, 1H), 7.94-7.98 (m,1H).

To a solution of Compound 28E (88 mg, 0.32 mmol) in THF (2 mL) was addedLiOH.H₂O (20 mg, 0.48 mmol), H₂O (2 mL) and MeOH (2 mL). The reactionmixture was stirred for 3 hours at 25° C., and then neutralized with 1 NHCl, It was evaporated to dryness, the resulted residue was dissolved inH₂O and extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, filtered, and evaporated to give Compound 28F (80 mg, yield100%). LCMS (m/z): 245 [M−1]⁻.

To a solution of Compound 28F (80 mg, 0.32 mmol) in DCM (10 mL) wasadded Intermediate A (88 mg, 0.32 mmol), HOBt (65 mg, 0.48 mmol) andEDCI (92 mg, 0.48 mmol). The mixture was stirred overnight at 25° C.,then washed with brine, dried over Na₂SO₄, filtered, evaporated, andpurified by prep-HPLC to give Compound 28 (31 mg, yield 19%) as a whitesolid. LC-MS (m/z): 507 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.11-2.17 (m, 4H), 2.89-3.01 (m, 2H),3.494-3.51 (m, 2H), 3.79-3.81 (m, 2H), 4.03-4.13 (m, 4H), 4.45-4.47 (m,1H), 5.08 (s, 1H), 6.72-6.74 (m, 1H), 6.82 (s, 1H), 7.17-7.19 (m, 2H),7.43-7.46 (m, 1H), 7.73-7.77 (m, 1H), 7.85-7.87 (m, 1H), 7.66-7.68 (m,1H), 11.94 (br, 1H).

Example 29

To a solution of Compound A8 (406 mg, 0.93 mmol) in CH₃CN (15 mL) wasadded 1-cyclopropylpiperazine (350 mg, 2.80 mmol), K₂CO₃ (387 mg, 2.80mmol) and NaI (100 mg). The mixture was heated at 82° C. for 2 h. It wascooled to rt and filtered. The filtrate was concentrated in vacuum togive a crude product Compound 29B (450 mg, crude) as a yellow oil. LCMS(m/z): 468 [M+1]⁺.

To a solution of Compound 29B (450 mg, 0.96 mmol) in EtOH/water (10 mL,9:1, v/v) was added LiOH.H₂O (126 mg, 2.88 mmol). After refluxedovernight, water (20 mL) was added to the mixture. It was extracted withethyl acetate (20 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuum to give a crude productCompound 29C (350 mg, crude) as a yellow oil. LCMS (m/z): 334 [M+1]⁺.

To a mixture of Compound 29C (100 mg, 0.30 mmol) in DCM (10 mL) wasadded EDCI (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) and IntermediateA (88 mg, 0.30 mmol) and stirred at 25° C. for 2 h. Water (10 mL) wasadded to the mixture, which was then extracted with DCM (20 mL×3), driedover anhydrous Na₂SO₄, and purified by prep-HPLC to yield atrifluoroacetic acid salt of Compound 29 (33 mg, yield 20%) as a whitesolid. LCMS (m/z): 562 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 0.87 (d, J=8 Hz, 2H), 1.17 (s, 2H), 2.45(s, 1H), 3.28 (d, J=16 Hz, 1H), 3.49-3.63 (m, 10H), 4.12-4.16 (m, 4H),4.54 (s, 1H), 4.84 (s, 1H), 6.78-6.86 (m, 4H), 7.35 (d, J=8 Hz, 1H),7.44 (d, J=8 Hz, 1H), 7.59 (s, 1H), 8.23 (d, J=8 Hz, 1H).

Example 30

A mixture of Compound 30A (10 g, 62 mmol), 2-bromo-1,1-dimethoxyethane(18.2 g, 108 mmol), Cs₂CO₃ (28 g, 86 mmol), NaI (100 mg) in DMF (10 mL)was stirred at 65° C. overnight. It was then cooled to rt and filtered.The filtrate was added water (200 mL), and extracted with ethyl acetate(100 mL×3). The combined extracts were washed with water (100 mL×3),brine (100 mL×1), and dried over Na₂SO₄. Filtration and concentration ofthe mixture gave rise to Compound 30B (10 g, yield 67%) as a yellowliquid. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 3.46(s, 6H), 4.03-4.05 (d, J=5.2 Hz, 2H), 4.72-4.74 (t, J=4.8 Hz, 1H),6.98-6.99 (d, J=8.8 Hz, 2H), 7.53-7.55 (d, J=8.8 Hz, 2H).

A solution of polyphosphoric acid (8.1 g, 24 mmol) in toluene (10 mL)was added compound 30B (5 g, 20 mmol) in toluene (10 mL) and the mixturewas stirred at 80° C. for 2 h. It was then poured into ice, stirred for30 min, and extracted with DCM (50 mL×3). The combined extracts werewashed with brine (50 mL×1), dried over Na₂SO₄, concentrated, andpurified by column chromatography on silica gel (petroleum, 100% v/v) toafford Compound 30C (690 mg, yield 19%) as a yellow solution inpetroleum. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)6.79 (s, 1H), 7.54 (m, 2H), 7.67 (s, 1H), 7.87 (s, 1H).

To a solution of Compound 30C (690 mg, 3.71 mmol) in petroleum etherfrom last step and anhydrous THF (10 mL) was added n-BuLi (2.5 M inhexane, 1.78 mL) at −78° C. under N₂. After stirred for 30 min, to themixture was added diethyl oxalate (2.7 g, 18.5 mmol). Stirred at −78° C.for 1 h, it was quenched with sat. aq NH₄Cl, and extracted with ethylacetate (50 mL×2). The combined extracts were washed with brine (50mL×1), dried over Na₂SO₄, concentrated and recrystallized from MeOH (3mL) to afford Compound 30D (500 g, yield 47%) as a yellow solid. ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.35-1.38 (t, J=7.2Hz, 3H), 4.37-4.43 (q, J=7.6 Hz, 2H), 7.93-8.03 (m, 2H), 8.34 (s, 1H),8.42-8.44 (m, 1H).

To a solution of Compound 30D (500 mg, 1.75 mmol) in DCM (10 mL) wasadded DAST (1.41 g, 8.76 mmol) at 0° C. and the mixture was stirred atrt for 1 h. It was poured into ice-water, added sat. NaHCO₃ (20 mL), andextracted with DCM (50 mL×2). The combined extracts were washed withbrine (50 mL×1), dried over Na₂SO₄, and concentrated. The crude productwas purified by column chromatography on silica gel (ethyl acetate inpetroleum, 4% v/v) to render Compound 30E (200 mg, yield 62%) as ayellow liquid. ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.36-1.39 (t, J=7.2 Hz, 3H), 4.39-4.45 (q, J=7.2 Hz, 2H), 7.23 (s,1H), 7.63-7.68 (m, 2H), 7.96 (s, 1H).

To a solution of Compound 30E (170 mg, 0.55 mmol) in EtOH (2 mL) wasadded LiOH.H₂O (28 mg, 0.66 mmol) in water (0.5 mL) and the mixture wasstirred at rt overnight. It was then adjusted pH to 4-5 with 1 N HCl,and extracted with ethyl acetate (50 mL×3). The combined extracts werewashed with brine (20 mL), dried over Na₂SO₄, and concentrated to giveCompound 30F (150 mg, yield 100%) as a yellow solid. LC-MS (m/z): 279[M−1]⁻.

A mixture of Compound 30F (60 mg, 0.21 mmol), EDCI (61 mg, 0.31 mmol),HOBt (48 mg, 0.31 mmol), Intermediate A (59 mg, 0.21 mmol) in DCM (5 mL)was stirred at 28° C. overnight before quenched with sat. aq NaHCO₃. Themixture was extracted with DCM (50 mL×2). The combined extracts werewashed with brine (50 mL×1), dried over Na₂SO₄, and concentrated. Thecrude product was purified by prep-HPLC to give Compound 30 (5 mg, yield4%) as a white solid. LC-MS (m/z): 541 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 2.13 (m, 4H), 2.70-3.02 (m, 2H),3.49-3.54 (m, 2H), 3.83 (m, 2H), 4.13-4.18 (m, 4H), 4.50 (m, 1H), 5.10(s, 1H), 6.75-6.84 (m, 4H), 7.60-7.67 (m, 2H), 7.88-7.92 (m, 2H), 11.96(s, 1H).

Example 31

A mixture of Compound 31A (3.00 g, 14.93 mmol),2-bromo-1,1-dimethoxyethane (2.77 g, 16.42 mmol) and K₂CO₃ (4.12 g,29.86 mmol) in DMF (26 mL) was stirred at 150° C. for 2 h. It wasevaporated to remove DMF. The residue was diluted with ethyl acetate(200 mL), washed with water and brine, dried with anhydrous Na₂SO₄, andevaporated to render Compound 31B (3.80 g, yield 88%) as a white solid.¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 4.10 (d,J=5.2 Hz, 2H), 4.75 (t, J=5.2 Hz, 1H), 6.89 (d, J=9.2 Hz, 1H), 7.61-7.64(m, 1H), 7.93 (s, 1H), 10.42 (s, 1H).

A mixture of Compound 31B (2.00 g, 6.90 mmol) in Acetic acid (50 mL) wasstirred at 120° C. overnight. The mixture was evaporated to removeAcetic acid, diluted with ethyl acetate (200 mL), washed with water andbrine, dried with anhydrous Na₂SO₄, and evaporated to yield Compound 31C(1.26 g, yield 81%) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 7.49-7.52 (m, 2H), 7.60-7.64 (m, 1H), 7.90(s, 1H), 9.89 (s, 1H).

To a solution of Compound 31C (2.00 g, 8.93 mmol) and NaCN (1.31 g,26.78 mmol) in MeOH (100 mL) was added Acetic acid (1.61 g, 26.78 mmol).The mixture was stirred at rt overnight. It was then quenched with sat.aq NaHCO₃ solution, diluted with ethyl acetate (200 mL), washed withwater and brine, and purified by silica gel column chromatography (ethylacetate in petroleum, 30% v/v) to provide Compound 31D (1.60 g, yield71%) as a colorless oil. LCMS: 252 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz)major characteristic peaks: δ (ppm) 6.10 (d, J=6.8 Hz, 1H), 7.06 (s,1H), 7.48-7.54 (m, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.93 (s, 1H).

A solution of Compound 31D (1.00 g, 3.98 mmol) in MeOH (20 mL) wasstirred at rt overnight with bubbling of HCl gas. The reaction wasquenched with H₂O (100 mL) and stirred at rt for 2 h. It was evaporatedto remove MeOH, diluted with ethyl acetate (150 mL), washed with waterand brine, dried with anhydrous Na₂SO₄, and evaporated to renderCompound 31E (900 mg, yield 82%) as a white solid. LCMS: 285 [M+1]⁺;¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 3.69 (s,3H), 5.41 (d, J=6.4 Hz, 1H), 6.52 (t, J=6.4 Hz, 1H), 6.90 (s, 1H),7.43-7.47 (m, 1H), 7.55-7.58 (m, 1H), 7.86 (s, 1H).

A suspension of Compound 31E (400 mg, 1.40 mmol) and DMP (712 mg, 1.68mmol) in DCM (20 mL) was stirred at rt overnight. It was quenched withsaturated aq Na₂S₂O₃, diluted with ethyl acetate (150 mL), washed withwater and brine, and purified by silica gel column chromatography elutedwith ethyl acetate in petroleum (from 10% to 20%, v/v) to give Compound31F (180 mg, yield 46%) as a white solid. LCMS: 283 [M+1]⁺; ¹H-NMR(DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 3.92 (s, 3H),7.77 (m, 2H), 8.19 (d, J=7.6 Hz, 2H).

To a solution of Compound 31F (500 mg, 1.77 mmol) in DCM (5 mL) wasadded DAST (1.42 g, 8.85 mmol). The mixture was stirred at rt overnight.The mixture was purified by column chromatography on silica gel elutedwith ethyl acetate in petroleum (10%, v/v) to yield Compound 31G (300mg, yield 55%) as a white solid. ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.95 (s, 3H), 7.55 (s, 1H), 7.65 (d, J=9.2Hz, 1H), 7.74 (d, J=9.6 Hz, 1H), 8.01 (s, 1H).

A mixture of Compound 31G (300 mg, 0.98 mmol) and LiOH.H₂O (123 mg, 2.94mmol) in MeOH/H₂O (10 mL/2 mL) was stirred at rt for 2 h. The mixturewas evaporated to remove MeOH. The residue was adjusted to pH 3 with 1 NHCl and filtered to afford Compound 31H (200 mg, yield 70%) as a whitesolid. LCMS: 289 [M−1]⁻.

A solution of Intermediate A (95 mg, 0.34 mmol), Compound 31H (100 mg,0.34 mmol), EDCI (98 mg, 0.51 mmol) and HOBt (67 mg, 0.51 mmol) in DCM(5 mL) was stirred at rt overnight. The mixture was diluted with ethylacetate (150 mL), washed with water and brine, dried with anhydrousNa₂SO₄, and purified by prep-HPLC to afford Compound 31 (100 mg, yield53%) as a white solid. LCMS: 551 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.12 (br s, 4H), 2.89-3.02 (m, 2H), 3.48(s, 2H), 3.81 (br s, 3H), 4.07-4.19 (m, 4H), 4.45-4.52 (m, 1H), 5.09 (s,1H), 6.73-6.76 (m, 3H), 6.83 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.39-7.50(m, 1H), 7.74 (s, 1H), 7.83 (s, 1H).

Example 32

To a solution of Compound A8 (437 mg, 1 mmol) in ACN (20 mL) was addedazetidine (171 mg, 3 mmol), K₂CO₃ (414 mg, 3 mmol) and NaI (449 mg, 3mmol). The mixture was heated at 82° C. overnight. It was cooled to rtand filtered. The filtration was concentrated in vacuum to give crudeproduct Compound 32A (330 mg, crude) as a yellow oil. LCMS (m/z): 399[M+1]⁺.

To a solution of Compound 32A (330 mg, 0.83 mmol) in EtOH/water (10 mL,9:1, v/v) was added LiOH.H₂O (104 mg, 2.48 mmol). The mixture wasrefluxed overnight. After reaction, water (20 mL) was added. It wasextracted with ethyl acetate (20 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuum to give a crudeproduct Compound 32B (170 mg, crude) as a yellow oil. LCMS (m/z): 265[M+1]⁺.

To a mixture of Compound 32B (150 mg, 0.57 mmol) in DCM (20 mL) wasadded EDCI (164 mg, 0.85 mmol), HOBt (115 mg, 0.85 mmol) and Compound11E (140 mg, 0.57 mmol) and stirred at 25° C. overnight. It was addedwater (10 mL), extracted with DCM (20 mL×3), dried over anhydrousNa₂SO₄, and purified by prep-HPLC and followed by prep-chiral-HPLC torender trifluoroacetic acid salts of Compound 32C (10 mg, yield 3.6%) asa white solid and Compound 32D (5 mg, yield 1.8%) as a white solid. ForCompound 32C, LCMS (m/z): 493 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.42 (s, 1H), 2.66 (s, 2H), 3.50-3.61 (m,2H), 4.06-4.14 (m, 6H), 4.23-4.30 (m, 3H), 4.12-4.16 (m, 4H), 4.63 (d,J=8 Hz, 1H), 6.56 (s, 1H), 6.73 (d, J=8 Hz, 1H), 6.80-6.85 (m, 3H), 7.37(d, J=8 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.61 (s, 1H); For Compound 32D,LCMS (m/z): 493 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 2.40 (s, 1H), 2.70 (s, 1H), 3.38 (s, 1H), 3.47 (d, J=8Hz, 2H), 4.10-4.17 (m, 5H), 4.20-4.30 (m, 3H), 4.89-4.90 (d, J=4 Hz,1H), 6.75 (s, 3H), 6.82 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.45 (d, J=8 Hz,1H), 7.60 (s, 1H).

Example 33

To a solution of Intermediate B (300 mg, 1 mmol) in DCM (15 mL) wasadded EDCI (288 mg, 1.5 mmol), HOBt (200 mg, 1.5 mmol), and Compound 11E(247 mg, 1 mmol). It was stirred at rt overnight. The mixture was addedDCM (20 mL), washed with water (50 mL×2), brine (50 mL×1), and driedover anhydrous Na₂SO₄. The residue was purified by prep-HPLC, followedby prep-chiral-HPLC to give Compound 33A (70 mg, yield 13%) as a whitefoam and Compound 33 (65 mg, yield 12%) as a white foam. For Compound33A, LC-MS (m/z): 525 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.09 (s, 4H), 2.87 (d, J=39.6 Hz, 2H),3.34 (s, 1H), 3.81 (s, 3H), 4.11 (m, 4H), 4.60 (s, 1H), 5.12 (s, 1H),6.45 (d, J=10.8 Hz, 1H), 6.91 (m, 2H), 7.32 (m, 1H), 7.41 (d, J=8.8 Hz,1H), 7.57 (d, J=2.4 Hz, 1H), 8.49 (d, J=6.8 Hz, 1H), 10.65 (s, 1H). ForCompound 33, LC-MS (m/z): 525 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.09 (s, 4H), 2.84 (d, J=44 Hz, 2H), 3.29(d, J=10.8 Hz, 1H), 3.73 (m, 3H), 4.12 (m, 4H), 4.58 (s, 1H), 5.14 (d,J=5.2 Hz, 1H), 6.47 (d, J=10.8 Hz, 1H), 6.94 (m, 2H), 7.32 (m, 1H), 7.42(d, J=8.8 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 8.60 (d, J=8 Hz, 1H), 11.06(s, 1H).

Example 34

To a solution of 6-bromoquinoline (7.9 g, 38 mmol) in THF (200 mL) wasadded n-BuLi (15 mL) at −60° C. under N₂ and after stirred for 0.5 h,Compound A4 (5 g, 13 mmol) in THF (10 mL) was added slowly. The reactionmixture was maintained at this temperature with stirring for 1 h, andthen added saturate aq NH₄Cl, extracted with ethyl acetate (100 mL×2),brine (100 mL), and dried over Na₂SO₄. The crude product was purified bycolumn chromatography on silica gel (ethyl acetate in petroleum, 10%v/v) to give Compound 34A (4.4 g, yield 75%) as a colorless liquid.LC-MS (m/z): 465 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 0.00 (s, 3H), 0.04 (s, 3H), 0.89 (s, 9H), 4.22 (m, 2H),5.33 (s, 2H), 5.40 (s, 1H), 7.55 (m, 5H), 8.37 (m, 4H), 8.66 (s, 1H),9.20 (m, 1H).

Compound 34A (4.4 g, 9.5 mmol) was dissolved in THF (60 mL) and cooleddown −80° C. under nitrogen atmosphere. L-Selectride (20 mL of 1Msolution in THF, 18.9 mmol) was added dropwise while keeping thetemperature at −80° C. After an hour, the reaction was quenched withsaturate aq NH₄Cl solution and the mixture was extracted with ethylacetate (50 mL×2), washed with brine (100 mL), and dried over Na₂SO₄.The crude product was purified by column chromatography on silica gel(ethyl acetate in petroleum, 10% v/v) to render Compound 34B (3 g, yield68%) as a colorless liquid. LC-MS (m/z): 466 [M+1]⁺; ¹H-NMR (CDCl₃, 400MHz) major characteristic peaks: δ (ppm) 0.03 (m, 6H), 0.92 (m, 9H),4.10 (m, 3H), 4.96 (m, 1H), 5.12 (s, 1H), 7.20 (s, 1H), 7.35 (m, 2H),7.41 (m, 1H), 7.62 (m, 1H), 7.88 (m, 1H), 8.18 (m, 2H), 8.91 (s, 1H).

Compound 34B (3 g, 6.4 mmol) was dissolved in THF (50 mL) at 0° C., tothis solution was added TBAF (839 mg, 3.2 mmol) at 0° C. The mixture wasstirred at rt overnight. It was condensed by evaporation of solvent,added water (50 mL), and extracted with ethyl acetate (50 mL×2), washedwith brine (100 mL), dried over Na₂SO₄, and concentrated. The residuewas suspended in a mixture of ethyl acetate in petroleum (10% v/v).Filtration gave Compound 34C (1.7 g, yield 75%) as a white solid. LC-MS(m/z): 466 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 3.72 (m, 3H), 4.89 (m, 4H), 5.63 (m, 1H), 6.80 (m, 1H), 7.15 (m,5H), 7.52 (m, 1H), 7.74 (m, 1H), 7.89 (s, 1H), 7.93 (m, 1H), 8.32 (m,1H), 8.87 (s, 1H).

Compound 34C (1 g, 2.8 mmol) was dissolved in THF (20 mL), to themixture was added TEA (860 mg, 8.5 mmol). The mixture was cooled to −15°C., to the mixture was added MsCl (360 mg, 3.1 mmol) slowly. Stirred atthis temperature for 30 min, the mixture was diluted with water,extracted with ethyl acetate (50 mL×2), washed with brine (50 mL), driedover Na₂SO₄, and concentrated to yield Compound 34D (1.2 g, crude),which was used for the next step without further purification. LC-MS(m/z): 431 [M+1]⁺.

To a solution of Compound 34D (1.2 g, 2.8 mmol) in THF (20 mL) was addedpyrrolidine (2 g, 28 mmol). The reaction mixture was allowed to warm upto rt and then heated at 50° C. overnight. The rude product was purifiedby column chromatography on silica gel (methanol in dichloromethane, 5%v/v) to give 34E (1 g, yield 91%). LC-MS (m/z): 406 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.88 (m, 4H), 2.77(s, 2H), 2.86 (m, 4H), 3.63 (m, 1H), 4.15 (m, 1H), 4.94 (s, 1H), 5.04(s, 1H), 7.15 (s, 1H), 7.24 (m, 4H), 7.39 (m, 1H), 7.68 (m, 1H), 7.85(m, 1H), 8.08 (m, 2H), 8.90 (m, 1H).

To a solution of Compound 34E (1 g, 2.5 mmol) in methanol (20 mL) wasadded Pd(OH)₂ (100 mg) and the mixture was stirred at rt under H₂overnight. Filtration and evaporation of the mixture gave Compound 34F(400 mg, yield 60%). LC-MS (m/z): 272 [M+1]⁺.

A mixture of Compound 11E (182 mg, 0.74 mmol), EDCI (212 mg, 1.1 mmol),HOBt (150 mg, 1.1 mmol), Compound 34F (200 mg, 0.74 mmol) in DCM (20 mL)was stirred at rt overnight. After added water, the mixture wasextracted with DCM (50 mL×2), washed with brine (50 mL), dried overNa₂SO₄, and concentrated. The crude product was purified by prep-HPLCand followed by chiral-prep-HPLC to give Compound 34G (46 mg, yield 13%)as a white solid and Compound 34 (58 mg, yield 16%) as a white solid.For Compound 34G, LC-MS (m/z): 500 [M+1]⁺. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.08 (s, 4H), 2.90 (m, 2H), 3.52 (m, 1H),3.64 (m, 2H), 3.94 (t, J=16.8 Hz, 1H), 4.71 (m, 2H), 5.14 (d, J=7.2 Hz,1H), 6.79 (s, 1H), 7.20 (m, 1H), 7.23 (s, 1H), 7.38 (s, 1H), 7.66 (m,1H), 8.06 (m, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.88(d, J=4.0 Hz, 1H), 9.43 (d, J=8.4 Hz, 1H), 11.56 (s, 1H); For Compound34, LC-MS (m/z): 500 [M+1]⁺. ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.16 (s, 2H), 3.05 (s, 2H), 3.74 (s, 3H),4.32 (s, 4H), 4.81 (s, 1H), 5.43 (s, 1H), 6.70 (s, 1H), 7.17 (m, 1H),7.24 (m, 1H), 7.34 (m, 1H), 7.66 (m, 1H), 7.90 (d, J=8.8 Hz, 1H), 8.05(s, 1H), 8.23 (m, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.96 (d, J=4.4 Hz, 1H),11.80 (s, 1H).

Example 35

To a solution of Compound A8 (847 mg, 2 mmol) in ACN (20 mL) was added4,4-difluoropiperidine (628 mg, 4 mmol), K₂CO₃ (414 mg, 3 mmol) and NaI(449 mg, 3 mmol). The mixture was heated at 82° C. overnight. It wascooled to rt, filtered and added ethyl acetate (30 mL). It was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuum togive a crude product Compound 35A (900 mg, crude) as a colorless solid.LCMS (m/z): 463 [M+1]⁺.

To a solution of Compound 35A (100 mg, 0.22 mmol) in EtOH/water (10 mL,9:1, v/v) was added LiOH.H₂O (28 mg, 0.66 mmol). The mixture wasrefluxed overnight, cooled down to rt, and added water (20 mL). It wasextracted with ethyl acetate (20 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuum to give crudeproduct Compound 35B (70 mg, crude) as a yellow oil. LCMS (m/z): 329[M+1]⁺.

To a mixture of Compound 35B (70 mg, 0.20 mmol) in DCM (10 mL) was addedEDCI (57 mg, 0.30 mmol), HOBt (40 mg, 0.30 mmol) and Compound 11E (49mg, 0.2 mmol) and stirred at 25° C. overnight. It was diluted with water(10 mL), extracted with DCM (20 mL×3), dried over anhydrous Na₂SO₄, andpurified by chiral-prep-HPLC to give Compound 35C (6.5 mg, yield 4.5%)as a white solid and Compound 35 (16.5 mg, yield 11.5%) as a whitesolid. For Compound 35C, LCMS (m/z): 557 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 2.32 (s, 4H), 3.16 (dd, J=4.12 Hz,2H), 3.81 (t, J=12 Hz, 1H), 4.14-4.20 (m, 5H), 4.55 (s, 1H), 4.89 (d,J=4 Hz, 1H), 6.77-6.84 (m, 2H), 6.89 (d, J=8 Hz, 2H), 7.32-7.37 (m, 1H),7.42 (d, J=8 Hz, 1H), 7.60 (s, 1H), 8.93 (d, J=8 Hz, 1H); For Compound35, LCMS (m/z): 557 [M+1]⁺; ¹H NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 2.38 (s, 4H), 3.33 (dd, J=4, 12 Hz, 2H), 3.52-3.58 (m,2H), 4.07-4.21 (m, 5H), 4.56 (s, 1H), 4.98 (s, 1H), 6.75 (s, 2H), 6.82(s, 2H), 7.35 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 7.59 (s, 1H), 7.94(d, J=8 Hz, 1H).

Example 36

To a solution of 3,3-dimethylpyrrolidine (645 mg, 4.79 mmol) in THF (15mL) was added Compound A8 (520 mg, 1.19 mmol) and TEA (1 mL). Thereaction mixture was stirred at 85° C. overnight. The solvents wereremoved and the residue was purified by prep-HPLC to afford the Compound36A (110 mg, yield 21%). LCMS: 441 [M+1]⁺.

To a solution of Compound 36A (110 mg, 0.25 mmol) in MeOH (5 mL) wasadded Pd(OH)₂ (15 mg). The reaction mixture was stirred at rt overnight,then filtered and evaporated to give Compound 36B (80 mg, yield 100%).LCMS: 307 [M+1]⁺.

A solution of Compound 36B (80 mg, 0.26 mmol), Compound 11E (64.5 mg,0.26 mmol), HOBT (53 mg, 0.39 mmol), EDCI (75 mg, 0.39 mmol) in DCM (10mL) was stirred at rt overnight. After added water (50 mL), the mixturewas extracted with DCM (50 mL×2). The combined organic phases were driedover Na₂SO₄, filtered, evaporated, and purified by chiral-prep-HPLC togive Compound 36C (13.8 mg, yield 10%) as a white solid and Compound 36D(10.4 mg, yield 7.5%) as a white solid. For Compound 36C, LCMS (m/z):535 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)1.09-1.31 (m, 6H), 1.84-1.94 (d, J=20 Hz, 2H), 2.46-2.52 (m, 1H),2.90-3.01 (m, 1H), 3.13-3.27 (m, 2H), 3.55-3.96 (m, 2H), 4.16-4.19 (m,4H), 4.43 (s, 1H), 4.90 (s, 1H), 6.76-6.78 (m, 1H), 6.82-6.91 (m, 3H),7.31-7.34 (m, 1H), 7.42-7.44 (m, 1H), 7.58-7.59 (m, 1H), 9.07-9.38 (m,1H), 11.85 (s, 1H); For Compound 36D, LCMS (m/z): 535 [M+1]⁺; ¹H NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.19-1.24 (m, 6H),1.90-2.00 (d, J=20 Hz, 2H), 2.65-2.83 (m, 1H), 3.07-3.09 (m, 1H), 3.42(s, 1H), 3.54 (s, 2H), 3.88 (s, 1H), 4.06-4.20 (m, 4H), 4.44 (s, 1H),5.08-5.12 (m, 1H), 6.72-6.75 (m, 3H), 6.83 (s, 1H), 7.32-7.35 (m, 1H),7.40-7.43 (m, 1H), 7.57-7.58 (m, 1H), 7.70-7.988 (m, 1H), 11.78-12.01(m, 1H).

Example 37

To a solution of Compound 37A (2 g, 8.3 mmol) in THF (30 mL) was addedn-BuLi (4 mL, 2.5 M) under N₂ at −60° C. The mixture was stirred for 1h, Compound 8C (2.2 g, 8.3 mmol) in THF (10 mL) was added. Stirred at rtfor 15 min, the mixture was diluted with aq NH₄Cl (40 mL), extractedwith ethyl acetate (50 mL×2), washed with brine (100 mL×2), andevaporated to dryness. The crude product was purified by columnchromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v)to give Compound 37B (1.4 g, yield 40%) as colorless oil. LC-MS (m/z):426 [M+1]⁺.

A solution of Compound 37B (1 g, 2.4 mmol) in THF (10 mL) and 1 N aq HCl(5 mL) was stirred at rt for 5 h. The mixture was quenched with water(10 mL), extracted with ethyl acetate (20 mL×2), washed with brine (30mL×2), and evaporated to dryness. The crude product was purified bycolumn chromatography silica gel (ethyl acetate in petroleum ether, 50%v/v) to afford Compound 37C (693 mg, yield 75%) as colorless oil. LC-MS(m/z): 386 [M+1]⁺.

To a solution of Compound 37C (0.5 g, 1.3 mmol) in THF (10 mL) was addedtriethylamine (0.26 g, 2.6 mmol) and MsCl (164 mg, 1.4 mmol) under N₂ at−40° C. The mixture was stirred at this temperature for 3 h, quenchedwith water (20 mL), extracted with ethyl acetate (30 mL×2), washed withbrine (50 mL×2), and evaporated to dryness. The crude product waspurified by column chromatography on silica gel (ethyl acetate inpetroleum ether, 50% v/v) to yield Compound 37D (0.42 g, yield 70%) ascolorless oil. LC-MS (m/z): 464 [M−17]⁺.

To a solution of Compound 37D (0.4 g, 0.86 mmol) in THF (10 mL) wasadded pyrrolidine (0.61 g, 8.6 mmol). The mixture was stirred at 60° C.overnight, quenched with water (20 mL), extracted with ethyl acetate (30mL×3), washed with brine (100 mL×2), and evaporated to dryness. Thecrude product was purified by column chromatography on silica gel (ethylacetate in petroleum ether, 50% v/v) to give Compound 37E (0.2 g, yield53%) as a colorless oil. LC-MS (m/z): 439 [M+1]⁺.

A solution of Compound 37E (0.2 g, 0.46 mmol) and LiOH.H₂O (57 mg, 1.4mmol) in ethanol (10 mL) was heated to reflux overnight. The mixture wasquenched with water (10 mL), extracted with ethyl acetate (20 mL×3),washed with brine (50 mL×2), and evaporated to dryness to give Compound37F (126 mg, yield 90%) as a colorless oil. LC-MS (m/z): 305 [M+1]⁺.

To a solution of Compound 37F (0.1 g, 0.33 mmol) in dichloromethane (10mL) was added Compound 11E (81 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol),HOBt (68 mg, 0.5 mmol). The mixture was stirred at rt overnight,quenched with water (20 mL), extracted with dichloromethane (20 mL×2),washed with brine (50 mL×2), and evaporated to dryness. The crudeproduct was purified by prep-HPLC and followed Chiral-HPLC to give twoisomers Compound 37G (11 mg) as a white solid and Compound 37 (6 mg) asa white solid. For Compound 37G, LC-MS (m/z): 533 [M+1]⁺, ¹H-NMR(DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 1.88 (m, 4H),3.11 (m, 2H), 3.52 (m, 4H), 4.31 (m, 1H), 4.60 (m, 1H), 6.22 (s, 1H),6.84 (s, 1H), 7.12 (m, 2H), 7.38 (m, 2H), 7.52 (m, 1H), 7.67 (m, 1H),7.78 (m, 1H), 9.28 (m, 1H), 9.82 (s, 1H). For Compound 37, LC-MS (m/z):533 [M+1]⁺, ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ(ppm) 1.87 (m, 4H), 3.10 (m, 2H), 3.50 (m, 4H), 4.51 (m, 1H), 4.89 (m,1H), 6.11 (s, 1H), 7.05 (m, 3H), 7.39 (m, 2H), 7.54 (m, 1H), 7.73 (m,1H), 7.82 (m, 1H), 8.94 (m, 1H), 9.63 (s, 1H).

Example 38

To a solution of (S)-3-fluoropyrrolidine (650 mg, 5.2 mmol) in CH₃CN (50mL) was added Na₂CO₃ (717 mg, 5.2 mmol) and it was stirred at rt for 30min. Compound A6 (756 mg, 1.73 mmol) was added and the reaction mixturewas heated to reflux overnight. It was poured into ice-water, extractedwith ethyl acetate (100 mL×2), washed with brine (100 mL×1), dried overNa₂SO₄, and evaporated to dryness. The crude product was purified byprep-HPLC to afford the Compound 38A (270 mg, yield 36%) as a yellowliquid. LCMS: 431 [M+1]⁺.

To a solution of Compound 38A (170 mg, 0.55 mmol) in EtOH (2 mL) wasadded LiOH.H₂O (79 mg, 1.89 mmol) in water (1 mL) and the mixture wasstirred at reflux overnight. It was quenched with H₂O (50 mL), extractedby ethyl acetate (50 mL×3), washed with brine (20 mL), dried overNa₂SO₄, and evaporated to dryness to give Compound 38B (200 mg, 100%) asa yellow oil. LC-MS (m/z): 297 [M+1]⁻.

A mixture of Compound 11E (165 mg, 0.67 mmol), EDCI.HCl (192 mg, 0.99mmol), HOBt (135 mg, 0.99 mmol), Compound 38B (200 mg, 0.67 mmol) in DCM(10 mL) was stirred at 28° C. overnight. The reaction was quenched withsat. aq NaHCO₃ (100 mL). The mixture was extracted with DCM (50 mL×2),washed with brine (50 mL×1), dried over Na₂SO₄, and evaporated todryness. The crude product was purified by prep-HPLC to give Compound 38(100 mg, yield 28%) as a white solid. LC-MS (m/z): 525 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.04-2.49 (m, 2H),3.21-3.97 (m, 6H), 4.06-4.20 (m, 4H), 4.52 (s, 1H), 5.04 (s, 1H),5.32-5.45 (d, J=52.4 Hz, 1H), 6.70-6.83 (m, 4H), 7.33-7.44 (m, 2H), 7.58(s, 1H), 7.74-7.76 (d, J=7.6 Hz, 1H).

Example 39

To a solution of Compound A8 (514 mg, 1.16 mmol) in THF (15 mL) wasadded (R)-2-methylpyrrolidine (400 mg, 4.7 mmol) and Et₃N (0.5 mL). Thereaction mixture was stirred at 85° C. overnight. After the removal ofsolvents, the residue was purified by prep-HPLC to afford the Compound39A (150 mg, yield 30%) as a white solid. LCMS: 427 [M+1]⁺.

To a solution of Compound 39A (150 mg, 0.35 mmol) in MeOH (5 mL) wasadded Pd(OH)₂ (15 mg). The reaction mixture was stirred in the presenceof H₂ at rt overnight. Filtration and evaporation of the solution led toCompound 39B (102 mg, yield 100%) as the colorless oil. LCMS: 293[M+1]⁺.

A solution of Compound 39B (102 mg, 0.35 mmol), Compound 11E (86.3 mg,0.35 mmol), HOBt (71.4 mg, 0.52 mmol), EDCI (100 mg, 0.52 mmol) in DCM(10 mL) was stirred at rt overnight. It was added water (50 mL),extracted with DCM (50 mL×2), dried over Na₂SO₄, filtered, andevaporated to dryness. The residue was purified by prep-HPLC to givedesired product Compound 39 (8.7 mg, yield 5%) as the colorless oil.LCMS (m/z): 521 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 1.25-1.49 (m, 3H), 1.97-2.11 (m, 2H), 2.25-2.26 (m, 2H),2.96-3.19 (m, 3H), 3.75-3.80 (m, 1H), 4.01 (s, 1H), 4.04-4.19 (m, 4H),4.46 (s, 1H), 5.23 (s, 1H), 6.64 (s, 1H), 6.69-6.79 (m, 2H), 6.84 (s,1H), 7.31-7.35 (m, 1H), 7.40-7.43 (m, 1H), 7.53-7.57 (m, 2H), 11.48 (s,1H).

Example 40

To a solution of (S)-2-methylpyrrolidine hydrochloride (540 mg, 4.4mmol) in CH₃CN (10 mL) was added Na₂CO₃ (600 mg, 4.4 mmol). Stirred atrt for 30 min, Compound A8 (437 mg, 1 mmol) was added. The reactionmixture was stirred at reflux overnight. It was poured into ice-water,extracted with ethyl acetate (100 mL×2), washed with brine (100 mL×1),dried over Na₂SO₄, and concentrated to afford the mixture of Compound40A (300 mg) as a yellow oil. LCMS: 427 [M+1]⁺.

To a solution of Compound 40A (300 mg) in EtOH (10 mL) was addedLiOH.H₂O (197 mg, 4.7 mmol) in water (5 mL) and the mixture was stirredreflux overnight. It was quenched in H₂O (50 mL) and the mixture wasextracted by ethyl acetate (50 mL×3), washed with brine (20 mL), driedover Na₂SO₄, and concentrated to render Compound 40B (326 mg, yield100%) as a yellow oil. LC-MS (m/z): 293 [M+1]⁺.

A mixture of Compound 40B (326 mg, 1.12 mmol), EDCI.HCl (233 mg, 1.66mmol), HOBt (164 mg, 1.66 mmol), Compound 11E (200 mg, 1.12 mmol) in DCM(10 mL) was stirred at 28° C. overnight. After quenched with sat. aqNaHCO₃ (100 mL), the mixture was extracted with DCM (50 mL×2), washedwith brine (50 mL×1), dried over Na₂SO₄, and concentrated. The crudeproduct was purified by prep-HPLC to give Compound 40 (126 mg, yield18%) as a white solid. LC-MS (m/z): 525 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400MHz) major characteristic peaks: δ (ppm) 1.31-1.33 (d, J=6.4 Hz, 3H),1.59-1.65 (m, 1H), 1.90-2.00 (m, 2H), 2.16-2.21 (m, 1H), 3.21-3.26 (m,1H), 3.42-3.61 (m, 4H), 4.06-4.16 (m, 4H), 4.45-4.47 (m, 1H), 4.66-4.67(m, 1H), 5.91 (s, 1H), 6.62-6.77 (m, 3H), 7.01 (s, 1H), 7.52-7.55 (m,1H), 7.75-7.77 (d, J=8.8 Hz, 1H), 7.83-7.85 (m, 1H), 8.92-8.99 (m, 2H).

Example 41

To a solution of 3,3-difluoropyrrolidine (384 mg, 3 mmol) in CH₃CN (20mL) was added Compound A8 (437 mg, 1 mmol), K₂CO₃ (414 mg, 3 mmol) andNaI (449 mg, 3 mmol). The mixture was heated at 82° C. overnight. It wascooled to rt, filtered and concentrated in vacuum to give a crudeproduct Compound 41A (250 mg, crude) as a yellow oil. LCMS (m/z): 449[M+1]⁺.

To a solution of Compound 41A (200 mg, 0.45 mmol) in EtOH/water (10 mL,9:1, v/v) was added LiOH.H₂O (93.6 mg, 2.23 mmol). The mixture wasrefluxed overnight. The mixture was diluted with water (20 mL) and thenextracted with ethyl acetate (20 mL×3), dried over anhydrous Na₂SO₄, andconcentrated in vacuum to give a crude Compound 41B (170 mg, crude) as ayellow oil. LCMS (m/z): 315 [M+1]⁺.

To a mixture of Compound 41B (150 mg, 0.47 mmol) in DCM (20 mL) wasadded EDCI (164 mg, 0.85 mmol), HOBt (115 mg, 0.85 mmol) and Compound11E (140 mg, 0.57 mmol) and stirred at 25° C. overnight. After theaddition of water (10 mL), the mixture was extracted with DCM (20 mL×3),dried over anhydrous Na₂SO₄, and purified by prep-HPLC to affordCompound 41 (40 mg) as a white solid. LCMS (m/z): 543 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.59 (s, 2H), 3.44(s, 1H), 3.60-3.74 (m, 4H), 4.07-4.15 (m, 4H), 4.46 (s, 1H), 4.99 (s,1H), 6.73-6.80 (m, 4H), 7.32-7.35 (m, 1H), 7.40-7.43 (d, 1H), 7.57 (d,1H), 7.78 (s, 1H).

Example 42

Compound A5 (4.64 g, 9.85 mmol) was dissolved in anhydrous THF (100 mL)and cooled down −30° C. under nitrogen atmosphere. CH₃MgBr (9.85 mL, 3Msolution in ether, 29.55 mmol) was added dropwise while keeping thetemperature at −30° C. Then the reaction was warmed to rt and stirredfor 3 hrs. The reaction was quenched with saturate aq NH₄Cl solution andextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed water, brine, and dried over Na₂SO₄. The crude product waspurified by column chromatography on silica gel (ethyl acetate inpetroleum, 10% v/v) to give Compound 42A (3.76 g, yield 78%) as a whitesolid. LC-MS (m/z): 193 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) −0.09 (s, 3H), −0.05 (s, 3H), 0.84 (s,9H), 1.42 (s, 3H), 3.51 (dd, J=2.0, 10.4 Hz, 1H), 3.53 (dd, J=2.0, 10.4Hz, 1H), 3.91 (d, J=7.2 Hz, 1H), 3.71 (m, 1H), 4.26 (s, 4H), 4.45 (m,1H), 5.16 (s, 2H), 5.72 (d, J=7.2 Hz, 1H), 6.85 (m, 2H), 6.95 (s, 1H),7.38 (m, 5H).

To a solution of Compound 42A (5.9 g, 12.11 mmol) in THF (120 mL) wasadded a solution of TBAF (1.58 g, 6.06 mmol) in THF (10 mL) at 0° C. andthe mixture was stirred at 25° C. overnight. The mixture was condensedby removal of solvent and added water (50 mL). It was extracted withethyl acetate (50 mL×3), washed with brine (100 mL×1), dried overNa₂SO₄. The crude product was purified by column chromatography onsilica gel (methanol in dichloromethane, 3% v/v) to give Compound 42B(3.2 g, yield 71%) as a yellow oil. LC-MS (m/z): 356 [M−17]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.49 (s, 3H), 3.34(s, 1H), 3.58 (m, 2H), 3.91 (d, J=8.8 Hz, 1H), 4.25 (s, 4H), 5.15 (s,2H), 5.79 (d, J=8.8 Hz, 1H), 6.85 (m, 2H), 6.96 (s, 1H), 7.38 (m, 5H).

To a solution of Compound 42B (3.2 g, 8.58 mmol) in THF (80 mL) wasadded Et₃N (2.6 g, 25.7 mmol) and the mixture was cooled to −40° C.,MsCl (0.7 mL, 9.01 mmol) was added slowly and kept with stirring at −40°C. about 0.5 h. Pyrrolidine (5.48 g, 77.2 mmol) was added to −40° C. Thereaction mixture was allowed to warm up to rt and then heated to 50° C.overnight. The mixture was added water (50 mL), extracted with ethylacetate (50 mL×3), washed with brine (100 mL×1), and dried over Na₂SO₄.The crude product was purified by column chromatography on silica gel(methanol in dichloromethane, 3% v/v) to give Compound 42C (2.52 g,yield 77%) as a white syrup. LC-MS (m/z): 356 [M−17]⁺; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 1.40 (s, 3H), 1.69 (m, 4H),2.35 (m, 1H), 2.57 (m, 1H), 4.16 (m, 1H), 4.27 (s, 4H), 5.15 (s, 2H),5.59 (d, J=10.2 Hz, 1H), 6.86 (m, 2H), 6.98 (s, 1H), 7.38 (m, 5H).

To a solution of Compound 42C (2.52 g, 5.92 mmol) in methanol (60 mL)was added Pd(OH)₂ (250 mg) and then the mixture was stirred at 25° C.under H₂ overnight. It was filtered and evaporated to render Compound42D (1.82 g, crude). LC-MS (m/z): 356 [M−17]⁺.

To a solution of compound 42D (200 mg, 0.68 mmol) and Compound 11E (168mg, 0.68 mmol) in DCM (210 mL) was added EDCI (197 mg, 1.03 mmol) andHOBt (139 mg, 1.03 mmol) under N₂. The mixture was stirred at 25° C.overnight. When TLC showed the starting material was consumed, water wasadded to the mixture. It was then extracted with DCM (50 mL×3). Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated to give a crude product. The crude product waspurified by prep-HPLC to give Compound 42 (145 mg, yield 41%) as a whitesolid. LC-MS (m/z): 521 (M+1)+, ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.52 (s, 3H), 1.99-2.06 (m, 4H), 2.60-2.74(m, 4H), 3.60-3.69 (m, 2H), 3.88 (t, J=7.2 Hz, 1H), 4.03 (m, 2H), 4.27(s, 4H), 4.61 (t, J=7.2 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 7.03 (s, 1H), 7.15 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.44 (d,J=8.4 Hz, 1H), 7.62 (s, 1H), 9.19 (d, J=8.4 Hz, 1H), 11.20 (s, 1H).

Example 43

To a stirred solution of Compound 43A (100 mg, 0.2 mmol), NaHCO₃ (33 mg,0.4 mmol) and NMP (126 mg, 0.3 mmol) in DCM (5 mL) was stirred at rt for2 h. The mixture was diluted with saturation aq NaHSO₃ (15 mL) andextracted with EtOAc (15 mL×3). The combined organic layers were washedwith saturate aq NaHSO₃ (15 mL), brine (15 mL), dried over Na₂SO₄, andconcentrated to give a crude product. The crude product was purified byprep-HPLC to afford Compound 43 (17 mg, yield 14%) as a white solid.LC-MS (m/z): 505 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 2.13 (s, 4H), 2.95-2.96 (m, 2H), 3.58-3.61 (m, 2H),3.89-3.99 (m, 2H), 4.06-4.23 (m, 4H), 5.47 (s, 1H), 6.70-6.72 (d, J=9Hz, 2H), 6.86 (s, 1H), 7.30-7.33 (m, 4H), 7.54 (s, 1H), 9.66-9.68 (d,J=8 Hz, 1H).

Example 44

To a solution of Compound 44A (3.73 g, 15.1 mmol) in THF (200 mL) wasadded n-BuLi (6.1 mL) at −60° C. under N₂ and it was stirred for 0.5 h,and then added slowly Compound A4 (2 g, 5.06 mmol) in THF (10 mL). Themixture was stirred at −60° C. for 1 h. After the addition of saturateaq NH₄Cl solution, the mixture was extracted with ethyl acetate (100mL×2), brine (100 mL), and dried over Na₂SO₄. The crude product waspurified by column chromatography on silica gel (ethyl acetate inpetroleum, 10% v/v) to yield Compound 44B (1.2 g, yield 47%) as acolorless oil. LC-MS (m/z): 504.2 [M+1]⁺.

Compound 44B (714 mg, 1.42 mmol) was dissolved in THF (9 mL) and cooleddown −80° C. under nitrogen atmosphere. L-Selectride (3 mL of 1Msolution in THF, 18.9 mmol) was added dropwise while keeping thetemperature at −80° C. After an hour, the reaction was quenched withsaturate aq NH₄Cl solution and extracted with ethyl acetate (50 mL×2),washed with brine (100 mL), and dried over Na₂SO₄. The crude product waspurified by column chromatography on silica gel (10% ethyl acetate inpetroleum) to give Compound 44C (350 g, yield 49%) as a colorless oil.LC-MS (m/z): 488.2 [M−17]⁺.

A solution of Compound 44C (2.08 g, 4.11 mmol) in THF (40 mL) was addedTBAF (537 mg, 2.06 mmol) at 0° C. and the mixture was stirred at rtovernight. The mixture was condensed and then added water (50 mL). Itwas extracted with ethyl acetate (50 mL×2), washed with brine (100 mL),dried over Na₂SO₄, and concentrated. The residue was suspended in amixture solution of ethyl acetate in petroleum (10% v/v). Filtrationgave Compound 44D (1 g, yield 65%) as a white solid. LC-MS (m/z): 374.1[M+1]⁺.

A solution of Compound 44D (0.9 g, 2.3 mmol) in THF (60 mL) was addedEt₃N (700 mg, 6.9 mmol) and the mixture was cooled to −15° C., to themixture was added MsCl (467 mg, 4.1 mmol) slowly. The mixture wasstirred at −15° C. about half an hour, and then diluted water. It wasextracted with ethyl acetate (50 mL×2), washed with brine (50 mL), driedover Na₂SO₄, and concentrated to give Compound 44E (1.12 g, crude),which was used for the next step without further purification. LC-MS(m/z): 452.1 [M+1]⁺.

To a solution of Compound 44E (1.12 g, 2.83 mmol) in THF (60 mL) wasadded pyrrolidine (2 g, 28 mmol). The reaction mixture was allowed towarm up to rt and then heated at 50° C. overnight. The crude product waspurified by column chromatography on silica gel (methanol indichloromethane, 5% v/v) to render Compound 44F (0.5 g, yield 50%).LC-MS (m/z): 445 [M+1]⁺.

To a solution of Compound 44F (520 mg, 1.17 mmol) in ethanol (12 mL) andwater (2 mL) was added LiOHH₂O (197 mg, 4.68 mmol). The mixture wasstirred at 80° C. overnight, diluted water, extracted with DCM (50mL×2), washed with brine (50 mL), dried over Na₂SO₄, and concentrated togive Compound 44G (360 mg, crude), which was used for the next stepwithout further purification. LC-MS (m/z): 311.1 [M+1]⁺.

A mixture of Compound 11E (149 mg, 0.60 mmol), EDCI (175 mg, 0.9 mmol),HOBt (150 mg, 1.1 mmol), Compound 44G (188 mg, 0.60 mmol) in DCM (10 mL)was stirred at rt overnight. The mixture was added water, extracted withDCM (50 mL×2), washed with brine (50 mL), dried over Na₂SO₄, andconcentrated. The crude product was purified by prep-HPLC and followedby chiral-prep-HPLC to give Compound 44H (23 mg, yield 7%) as a whitesolid and Compound 44 (22 mg, yield 7%) as a white solid. For Compound44H, LC-MS (m/z): 539.1 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 0.72-0.79 (m, 4H), 2.06 (s, 4H), 2.78-3.20(m, 6H), 3.60-3.93 (m, 4H), 4.50 (s, 1H), 4.93-4.95 (d, J=5.6 Hz, 1H),6.83 (s, 1H), 7.10-7.12 (d, J=8.4 Hz, 1H), 7.20-7.22 (d, J=8.0 Hz, 1H),7.30-7.33 (dd, J=2.0, 8.8 Hz, 1H), 7.40-7.42 (m, 2H), 7.56-7.57 (d,J=2.0 Hz, 1H), 9.07-9.09 (d, J=8.0 Hz, 1H). For Compound 44, LC-MS(m/z): 539.1 [M+1]⁺; ¹H NMR (CDCl₃, 400 MHz) major characteristic peaks:δ (ppm) 0.72-0.77 (m, 4H), 2.08-2.14 (d, J=24.4 Hz, 4H), 2.94-3.02 (d,J=34.4 Hz, 5H), 3.53-3.58 (m, 3H), 3.81-3.82 (d, J=2.4 Hz, 2H),4.48-4.50 (d, J=9.6 Hz, 1H), 5.14 (s, 1H), 6.71 (s, 1H), 7.04-7.06 (d,J=8.4 Hz, 1H), 7.12-7.14 (d, J=8.4 Hz, 1H), 7.32-7.41 (m, 3H), 7.56 (s,1H), 7.88-7.90 (d, J=7.2 Hz, 1H).

Example 45

To a solution of Compound 43A (100 mg, 0.2 mmol) in DCM (10 mL) wasadded SOCl₂ (0.1 mL). The mixture was stirred at 25° C. for 3 h, andconcentrated to afford the Compound 45A (105 mg) as a yellow liquid.LCMS (m/z): 525 [M+1]⁺.

A solution of NH₂OCH₃ in MeOH (30%, m/v, 1 mL) was added to the Compound45A (105 mg, 0.2 mmol). The mixture was stirred at 25° C. for 3 h. Afterreaction, the mixture was concentrated. The crude product was purifiedby prep-HPLC to give Compound 45 (15 mg, yield 15%) as a white solid.LC-MS (m/z): 536 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 1.82 (m, 4H), 2.72 (m, 5H), 2.91-2.96 (m, 1H), 3.76 (s,3H), 4.06-4.07 (m, 1H), 4.23-4.27 (m, 4H), 4.94 (d, J=2.4 Hz, 1H),5.26-5.28 (d, J=10.8 Hz, 1H), 6.72 (s, 1H), 6.75-6.81 (m, 2H), 6.86 (s,1H), 7.31-7.34 (m, 1H), 7.43-7.45 (m, 1H), 7.55-7.56 (m, 1H).

Example 46

To a solution of (R)-3-fluoropyrrolidine (174 mg, 1.38 mmol) in CH₃CN(10 mL) was added K₂CO₃ (190 mg, 1.38 mmol). Stirred at rt for 30 min,Compound A8 (200 mg, 0.46 mmol) was added. The reaction mixture wasstirred at reflux overnight. It was poured into ice-water, extractedwith ethyl acetate (100 mL×2), washed with brine (100 mL×1), dried overNa₂SO₄, and concentrated to give a crude Compound 46A (200 mg, 100%),which was used for the next step without further purification. LC-MS(m/z): 431 [M+1]⁺.

To a solution of Compound 46A (200 mg, 0.62 mmol) in EtOH (10 mL) wasadded LiOH.H₂O (130 mg, 3.1 mmol) in water (10 mL) and the mixture wasstirred at reflux overnight. It was poured into H₂O (50 mL), extractedwith ethyl acetate (50 mL×3), washed with brine (20 mL), dried overNa₂SO₄, and concentrated to yield a crude Compound 46B (170 mg, yield100%) as a yellow oil. LC-MS (m/z): 297 [M+1]⁺.

A mixture of Compound 11E (140 mg, 0.57 mmol), EDCI (160 mg, 0.84 mmol),HOBt (113 mg, 0.84 mmol) and Compound 46B (170 mg, 0.57 mmol) in DCM (20mL) was stirred at 28° C. overnight. The mixture was added sat. NaHCO₃(100 mL), extracted with DCM (50 mL×2), washed with brine (50 mL×1),dried over Na₂SO₄, and concentrated. The crude product was purified byprep-HPLC to give Compound 46 (60 mg, 20%) as a white solid. LC-MS(m/z): 525 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.08-2.39 (m, 2H), 3.19-3.86 (m, 6H), 4.03-4.14 (m, 4H), 4.49 (s,1H), 4.71 (s, 1H), 5.38-5.54 (d, J=48.4 Hz, 1H), 5.91 (s, 1H), 6.64-6.72(m, 3H), 6.96-6.99 (m, 1H), 7.52-7.55 (m, 1H), 7.71-7.83 (m, 2H),8.82-8.89 (m, 1H), 10.33 (s, 1H).

Example 47

To a solution of Compound 47A (12.6 g, 45.5 mmol) in THF (300 mL) wasadded n-BuLi (18.3 mL) at −60° C. under N₂ and it was stirred for 0.5 h,and then slowly added A4 (6 g, 15.2 mmol) in THF (40 mL). The mixturewas stirred at −60° C. for 1 h, and followed by the addition of saturateaq NH₄Cl solution. It was extracted with ethyl acetate (300 mL×2), brine(200 mL), dried over Na₂SO₄. The crude product was purified by columnchromatography on silica gel (ethyl acetate in petroleum, 10 v/v) togive Compound 47B (4 g, yield 50%) as a colorless oil. LC-MS (m/z):534.2 [M+1]⁺.

Compound 47B (4.05 g, 7.6 mmol) was dissolved in THF (48 mL) and cooleddown to −80° C. under nitrogen atmosphere. L-Selectride (16 mL of 1Msolution in THF, 15 mmol) was added dropwise while keeping thetemperature at −80° C. After an hour, the reaction was quenched withsaturate aq NH₄Cl solution and then extracted with ethyl acetate (200mL×2), washed with brine (200 mL), and dried over Na₂SO₄. The crudeproduct was purified by column chromatography on silica gel (ethylacetate in petroleum, 10% v/v) to give Compound 47C (3.2 g, 79%) as acolorless oil. LC-MS (m/z): 518.2 [M−17]⁺.

A solution of Compound 47C (3.2 g, 5.98 mmol) in THF (40 mL) was addedTBAF (780 mg, 3 mmol) at 0° C. The mixture was stirred at rt overnight,condensed by removal of solvents, and added water (150 mL). It wasextracted with ethyl acetate (250 mL×2), washed with brine (100 mL),dried over Na₂SO₄, concentrated. The residue was suspended in a solutionof ethyl acetate in petroleum (10% v/v). filtration of the suspensiongave Compound 47D (2.25 g, yield 89%) as a white solid. LC-MS (m/z):422.1 [M+1]⁺.

A solution of Compound 47D (2.25 g, 5.34 mmol) in THF (120 mL) was addedEt₃N (1.63 g, 16 mmol) and MsCl (1.08 g, 9.43 mmol) slowly at −15° C.The mixture was stirred about half an hour, and then diluted water,extracted with ethyl acetate (200 mL×2), washed with brine (150 mL),dried over Na₂SO₄, and concentrated to render Compound 47E (2.3 g,crude), which was used for the next step without further purification.LC-MS (m/z): 482 [M-17]⁺.

To a solution of Compound 47E (2.3 g, 4.61 mmol) in THF (60 mL) wasadded pyrrolidine (3.5 g, 49 mmol). The reaction mixture was allowed towarm up to rt and then heated at 50° C. overnight. The crude product waspurified by column chromatography on silica gel (methanol indichloromethane, 5% v/v) to give Compound 47F (0.52 g, yield 23.8%).LC-MS (m/z): 475 [M+1]⁺.

To a solution of Compound 47F (520 mg, 1.1 mmol) in ethanol (12 mL) andwater (2 mL) was added LiOHH₂O (197 mg, 4.68 mmol). The mixture wasstirred at 80° C. overnight, and then diluted water, extracted with DCM(150 mL×2), washed with brine (150 mL), dried over Na₂SO₄, andconcentrated to afford Compound 47G (360 mg, crude), which was used forthe next step without further purification. LC-MS (m/z): 341.2 [M+1]⁺.

A mixture of Compound 11E (149 mg, 0.60 mmol), EDCI (175 mg, 0.9 mmol),HOBt (150 mg, 1.1 mmol), Compound 47G (206 mg, 0.60 mmol) in DCM (10 mL)was stirred at rt overnight. The mixture was added water, extracted withDCM (150 mL×2), washed with brine (100 mL), dried over Na₂SO₄, andconcentrated. The crude product was purified by prep-HPLC and followedby chiral-prep-HPLC to give Compound 47H (13 mg, yield 4%) as a whitesolid and Compound 47 (31 mg, 10.5%) as a white solid. For Compound 47H,LC-MS (m/z): 569.2 [M+1]⁺; ¹H NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 2.05-2.81 (m, 6H), 2.78-2.89 (m, 5H), 3.21-3.22 (d, J=4.0Hz, 1H), 3.62 (s, 1H), 3.75 (S, 1H), 3.90-4.02 (m, 5H), 4.50 (s, 1H),4.77 (s, 1H), 4.90 (s, 1H), 6.63-6.66 (dd, J₁=5.2 Hz, J₂=8.0 Hz, 1H),6.80-6.81 (d, J=4.8 Hz, 1H), 7.17-7.19 (d, J=8.0 Hz, 1H), 7.30-7.32 (m,1H), 7.38-7.41 (dd, J₁=3.2 Hz, J₂=8.0 Hz, 1H), 7.44-7.46 (d, J=6.4 Hz,1H), 7.55-7.56 (m, 1H), 9.14 (s, 1H), 11.57 (s, 1H). For Compound 47,LC-MS (m/z): 569.2 [M+1]⁺; ¹H NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 2.02-2.11 (m, 6H), 2.97-3.02 (m, 2H), 3.50 (s, 1H),3.69-4.12 (m, 9H), 4.56 (m, 1H), 4.71 (s, 1H), 5.10 (s, 1H), 6.55-6.57(d, J=8.0 Hz, 1H), 6.63-6.65 (d, J=7.6 Hz, 1H), 7.09-7.11 (d, J=7.2 Hz,1H), 7.31-7.40 (m, 3H), 7.55 (Is, 1H), 8.06 (s, 1H), 11.48 (s, 1H).

Example 48

To a solution of 2-azaspiro [3.3] heptane (100 mg, 1.0 mmol) in CH₃CN(10 mL) was added K₂CO₃ (414 mg, 3.0 mmol) and Compound A6 (437 mg, 1.0mmol). The reaction mixture was stirred at reflux overnight. It waspoured into ice-water, extracted with ethyl acetate (20 mL×2), washedwith brine (20 mL×1), dried over Na₂SO₄, and concentrated to afford theCompound 48A (180 mg, yield 40%) as a yellow liquid. LC-MS (m/z): 439[M+1]⁺.

To a solution of Compound 48A (180 mg, 0.4 mmol) in EtOH (3 mL) wasadded LiOH.H₂O (84 mg, 2.0 mmol) in water (1 mL) and the mixture wasstirred at reflux overnight. The mixture was diluted with H₂O (30 mL),extracted by ethyl acetate (30 mL×3), washed with brine (20 mL), driedby Na₂SO₄, and concentrated to render Compound 48B (100 mg, yield 80%)as a yellow oil. LC-MS (m/z): 305 [M+1]⁺.

A mixture of Compound 11E (81 mg, 0.3 mmol), EDCI (76 mg, 0.4 mmol),HOBt (54 mg, 0.4 mmol), Compound 48B (100 mg, 0.3 mmol) in DCM (5 mL)was stirred at 28° C. overnight. After the addition of sat. aq NaHCO₃(100 mL), the mixture was extracted with DCM (30 mL×2), washed withbrine (30 mL×1), dried over Na₂SO₄, and concentrated. The crude productwas purified by prep-HPLC to give Compound 48 (14 mg, yield 8%) as awhite solid. LC-MS (m/z): 533 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.83-1.88 (m, 2H), 2.15 (s, 2H), 2.34 (s,2H), 3.34 (s, 2H), 3.78-3.84 (m, 2H), 4.06-4.19 (m, 4H), 4.28-4.38 (m,3H), 5.01 (s, 1H), 6.74-6.81 (m, 4H), 7.34-7.7.36 (m, 1H), 7.42-7.44 (m,1H), 7.58-7.58 (m, 1H), 7.84-7.86 (m, 1H), 12.29-12.30 (m, 1H).

Example 49

To a solution of 5-bromo-1-methyl-1H-indazole (3.2 g, 15 mmol) in THF(50 mL) was added n-BuLi (7.2 mL, 2.5 M) under N₂ at −60° C. The mixturewas stirred for 1 h, Compound 8C (1.3 g, 5 mmol) in THF (10 mL) wasadded. After stirred at rt for 3 h, the mixture was diluted with aqNH₄Cl (40 mL) solution, extracted with ethyl acetate (50 mL×2), washedwith brine (100 mL×2), and evaporated. The crude product was purified bycolumn chromatography on silica gel (ethyl acetate in petroleum ether,30% v/v) to give Compound 49A (1.0 g, yield 51%) as a colorless oil.LC-MS (m/z): 396 [M+1]⁺.

A solution of Compound 49A (0.5 g, 1.3 mmol) in THF (20 mL) and 1 N aqHCl (4 mL) was stirred at rt for 5 h. The mixture was quenched withwater (10 mL), extracted with ethyl acetate (20 mL×2), washed with brine(30 mL×2), and evaporated to remove the solvents. The crude product waspurified by column chromatography on silica gel (ethyl acetate inpetroleum ether, 50% v/v) to give Compound 49B (374 mg, yield 81%) as acolorless oil. LC-MS (m/z): 356 [M+1]⁺.

To a solution of Compound 49B (1 g, 2.8 mmol) in THF (25 mL) was addedtriethylamine (0.44 g, 4.4 mmol) and MsCl (0.4 g, 3.5 mmol) under N₂ at−40° C. The mixture was stirred at this temperature for 3 h, quenchedwith water (40 mL), extracted with ethyl acetate (50 mL×3), washed withbrine (100 mL×2), NS evaporated to dryness. The crude product waspurified by column chromatography on silica gel (ethyl acetate inpetroleum ether, 50% v/v) to give Compound 49C (0.87 g, yield 72%) as acolorless oil. LC-MS (m/z): 416 [M−17]⁺.

To a solution of Compound 49C (0.8 g, 1.8 mmol) in THF (25 mL) was addedpyrrolidine (1.3 g, 18 mmol). The mixture was stirred at 60° C.overnight, quenched with water (40 mL), extracted with ethyl acetate (50mL×3), washed with brine (100 mL×2), and evaporated to dryness. Thecrude product was purified by column chromatography on silica gel (ethylacetate in petroleum ether, 50% v/v) to give Compound 49D (0.4 g, yield55%) as colorless oil. LC-MS (m/z): 409 [M+1]⁺.

A solution of Compound 49D (0.4 g, 1 mmol) and LiOH.H₂O (157 mg, 3.6mmol) in ethanol (20 mL) was heated to reflux overnight. After theaddition of water (40 mL), the mixture was extracted with ethyl acetate(50 mL×3), washed with brine (100 mL×2), evaporated to give Compound 49E(247 mg, yield 90%) as a colorless oil. LC-MS (m/z): 275 [M+1]⁺.

To a solution of Compound 49E (0.2 g, 0.73 mmol) in dichloromethane (15mL) was added Compound 11E (222 mg, 0.9 mmol), EDCI (216 mg, 1.13 mmol),HOBt (152 mg, 1.13 mmol). The mixture was stirred at rt overnight,quenched with water (20 mL), extracted with dichloromethane (20 mL×2),washed with brine (50 mL×2), and evaporated to dryness. The crudeproduct was purified by prep-HPLC and followed by chira-prepl-HPLC togive two isomers Compound 49F (5 mg) as white solid and Compound 49 (5mg) as white solid. For Compound 49F, LC-MS (m/z): 503 [M+1]⁺, ¹H-NMR(DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 1.88 (m, 4H),3.14 (m, 2H), 3.58 (m, 2H), 3.68 (m, 1H), 3.92 (s, 3H), 4.44 (m, 1H),4.66 (m, 1H), 6.12 (s, 2H), 7.47 (m, 5H), 7.63 (s, 1H), 7.92 (s, 1H),9.27 (s, 1H), 9.70 (s, 1H); For Compound 49, LC-MS (m/z): 503 [M+1]⁺,¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 2.0 (m,6H), 3.17 (m, 3H), 3.50 (m, 3H), 3.98 (m, 4H), 4.60 (s, 1H), 4.96 (s,1H), 6.05 (s, 1H), 6.69 (s, 1H), 7.57 (m, 9H), 7.88 (s, 1H), 8.92 (s,1H), 9.65 (s, 1H).

Example 50

To a stirred solution of Compound 50A (500 mg, 2.21 mmol) in dioxane (10mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (618 mg,2.43 mmol), KOAc (694 mg, 7.08 mmol) and Pd(PPh₃)₂Cl₂ (90 mg, 0.11 mmol)under N₂. The mixture was stirred at 90° C. overnight. The reactionmixture was evaporated to remove the solvent. The residue was dilutedwith ethyl acetate (100 mL), washed with water, brine, and dried overanhydrous Na₂SO₄. Filtration and evaporation of the solvents gaveCompound 50B (606 mg, yield 100%) as a brown oil which was used for thenext step without purification. LCMS: (m/z) 275 [M+1]⁺;

To a stirred solution of Compound 50B (606 mg, 2.21 mmol) in dioxane (10mL) was added Pd(PPh₃)₄ (127 mg, 0.11 mmol), 2-bromopyridine (384 mg,2.43 mmol) and 3 mL of 30% aq NaOH under N₂. The mixture was stirred at90° C. overnight. The mixture was evaporated to remove the solvents. Theresidue was diluted with ethyl acetate (100 mL), washed with water,brine, and dried over anhydrous Na₂SO₄. The crude was purified by columnchromatography on silica gel (methanol in DCM, 5% v/v) to renderCompound 50C (230 mg, yield 46%, two steps) as a yellow oil. LCMS: (m/z)226 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)1.58 (brs, 1H), 2.76-2.85 (m, 3H), 3.10-3.18 (m, 2H), 3.69 (d, J=6.0 Hz,2H), 7.20 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.71-7.75 (m, 3H), 7.86 (s,1H), 8.67 (d, J=4.8 Hz, 1H).

To a stirred solution of Compound 50C (230 mg, 1.02 mmol) in DCM (10 mL)was added DMP (520 mg, 1.23 mmol). The mixture was stirred at rt for 3h. The reaction mixture was quenched with sat. aq Na₂SO₃ solution. Theaqueous phase was extracted with DCM (50 mL×3). The combined organicphase was washed with water, brine, and dried over anhydrous Na₂SO₄. Thecrude was purified by column chromatography on silica gel (ethyl acetatein petroleum ether, 34% v/v) to give Compound 50D (200 mg, yield 88%) ascolorless oil. LCMS: (m/z) 224 [M+1]⁺.

To a stirred solution of Compound 50D (200 mg, 0.90 mmol) in H₂O (10 mL)was added NaS₂O₅ (170 mg, 0.90 mmol). The mixture was stirred at rt for3 h, and NaCN (88 mg, 1.79 mmol) was added to the mixture. After stirredat rt overnight, the mixture was extracted with ethyl acetate (100mL×3). The combined organic phase was washed with water, brine, anddried over anhydrous Na₂SO₄. Filtration and evaporation of the solventsgave Compound 50E (180 mg, yield 80%) as a white solid. LCMS: (m/z) 251[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)2.86-3.03 (m, 3H), 3.15-3.18 (m, 3H), 4.28 (d, J=4.2 Hz, 1H), 7.30 (m,2H), 7.65-7.69 (m, 2H), 7.77-7.80 (m, 2H), 8.70 (d, J=2.8 Hz, 1H).

A solution of Compound 50E (1.88 g, 7.52 mmol) in ethanol (80 mL) wasbubbled with a gentle stream of HCl gas (dried over cone H₂SO₄) for 6 hand left to stand overnight at 4° C. The mixture was added water (30 mL)and stirred at 80° C. for 2 h. After cooled down to rt, the mixture wasextracted with ethyl acetate (100 mL×3). The combined organic phase waswashed with water, brine, and dried over anhydrous Na₂SO₄, and purifiedby column chromatography on silica gel (methanol in dichloromethane, 3%v/v) to yield Compound 50F (1.17 g, yield 52%) as a yellow solid. LCMS:(m/z) 298 [M+1]⁺.

To a stirred solution of Compound 50F (210 mg, 0.71 mmol) in DCM (11 mL)was added NaHCO₃ (119 mg, 1.41 mmol), and DMP (360 mg, 0.85 mmol) at 0°C. The mixture was stirred at 0° C. for one hour. The reaction mixturewas quenched with sat. aq Na₂SO₃ solution. The aqueous phase wasextracted with DCM (50 mL×3). The combined organic phase was washed withwater, brine, and dried over anhydrous Na₂SO₄. The crude was purified bycolumn chromatography on silica gel (methanol in dichloromethane, 3%v/v) to afford Compound 50G (180 mg, yield 86%) as yellow oil. LCMS:(m/z) 224 [M+1]⁺.

To a stirred solution of Compound 50G (233 mg, 0.79 mmol) in DCM (10 mL)was added DAST (720 mg, 4.47 mmol). The mixture was stirred at rtovernight. After cooled down to rt, the mixture was poured into waterand then extracted with ethyl acetate (100 mL×3). The combined organicphase was washed with water, brine, and dried over anhydrous Na₂SO₄,purified by column chromatography on silica gel (methanol indichloromethane, 5% v/v) to give Compound 50H (140 mg, yield 56%) as ayellow oil. LCMS: (m/z) 318 [M+1]⁺.

To a stirred solution of Compound 50H (140 mg, 0.44 mmol) in THF (10 mL)was added LiOH.H₂O (37 mg, 0.88 mmol) and water (2 mL). The mixture wasstirred at rt for 3 h. The mixture was acidified to pH 1 with 1M HCl andevaporated. The aqueous phase was extracted with ethyl acetate (50mL×3). The combined organic phase was washed with water, brine, anddried over anhydrous Na₂SO₄, concentrated to give Compound 501 (110 mg,yield 86%) as a yellow oil. LCMS: (m/z) 290 [M+1]⁺.

To a solution of Compound 501 (110 mg, 0.38 mmol) in DCM (10 mL) wasadded EDCI (110 mg, 0.57 mmol), HOBt (77 mg, 0.57 mmol), Intermediate A(106 mg, 0.38 mmol). Then it was stirred at rt overnight. The mixturewas added DCM (20 mL), washed with water (50 mL×2) and brine (50 mL×1),dried over anhydrous Na₂SO₄, concentrated, and purified by prep-HPLCtwice to give Compound 50 (1.6 mg, yield 1%) as a colorless oil. LC-MS(m/z): 550 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.95 (m, 4H), 2.68-2.96 (m, 5H), 3.29-3.38 (m, 2H), 3.76 (s, 2H),4.11 (s, 4H), 4.37 (s, 1H), 5.08 (m, 1H), 5.28 (s, 1H), 6.79-6.85 (m,3H), 7.30 (s, 1H), 7.47 (m, 1H), 7.65 (m, 3H), 7.92 (m, 1H), 8.24 (m,1H), 8.96 (m, 1H), 11.79 (s, 1H).

Example 51

To a solution of 2-azabicyclo [2.2.1] heptane (132 mg, 1 mmol) in MeCN(10 mL) was added K₂CO₃ (69 mg, 0.5 mmol) and Compound A8 (219 mg, 0.5mmol). The mixture was stirred at 70° C. for 48 h. After evaporation toremove solvents, the residue was dissolved in H₂O, extracted with ethylacetate; the combined organic layers were dried over anhydrous Na₂SO₄.After filtration and evaporation, a crude Compound 51A (210 mg) wasobtained as an oil, which was used for the next step directly. LCMS(m/z): 331 [M+1]⁺.

To a solution of Compound 51A (210 mg, 0.64 mmol) in EtOH (9 mL) and H₂O(9 mL) was added LiOH.H₂O (267 mg, 6.4 mmol). The reaction mixture wasrefluxed for 24 h. After removal of the solvents, the residue wasdissolved in H₂O, extracted with ethyl acetate, and dried over Na₂SO₄ togive Compound 51B (190 mg), which was used for the next step withoutpurification. LCMS (m/z): 305 [M+1]⁺.

To a solution of Compound 51B (91 mg, 0.3 mmol) in DCM (12 mL) was addedCompound 11E (111 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) and EDCI (86mg, 0.45 mmol). The mixture was stirred for 12 h at 25° C. The mixturewas washed with brine and dried over anhydrous Na₂SO₄. After filtrationand evaporation, the residue was purified by prep-HPLC to give Compound51 (38 mg, yield 19%) as a white solid. LC-MS (m/z): 507 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.52-1.90 (m, 4H),2.04-2.24 (m, 1H), 2.57-2.98 (m, 2H), 3.30-3.72 (m, 3H), 4.07-4.50 (m,8H), 5.01-5.16 (m, 1H), 6.68-6.83 (m, 4H), 7.33-7.35 (m, 1H), 7.42-7.44(m, 1H), 7.57 (d, J=1.2 Hz, 1H), 8.02-8.17 (m, 1H), 10.21-10.33 (m, 1H).

Example 52

To a solution of ethyl 2-(diethoxyphosphoryl) acetate (10.77 g, 48.08mmol) in THF (50 mL) was added t-BuOK (5.38 g, 48.08 mmol) at roomtemperature. After stirred for 30 min, Compound 52A (5.00 g, 32.05 mmol)was added. The mixture was stirred at room temperature overnight. It wasdiluted with ethyl acetate (200 mL), washed with water and brine, andpurified with silica gel column chromatography (ethyl acetate inpetroleum ether, 10% v/v) to render Compound 52B (6.60 g, yield 91%) asa colorless oil. LC-MS (m/z): 227 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.36 (t, J=7.2 Hz, 3H), 426-4.32 (m, 2H),6.55 (d, J=15.6 Hz, 1H), 7.5-7.53 (m, 2H), 7.65-7.69 (m, 1H), 7.83-7.87(m, 4H).

A suspension of Pd/C (1.00 g, 10%) and Compound 52B (7.30 g, 32.0 mmol)in MeOH (100 mL) was stirred at room temperature overnight under H₂. Themixture was filtered to remove Pd/C. The filtrate was evaporated toyield Compound 52C (7.30 g, yield 100%) as a colorless oil. LC-MS (m/z):229 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)1.23 (t, J=7.2 Hz, 3H), 2.71 (t, J=7.6 Hz, 2H), 3.12 (t, J=8.4, 2H),4.10-4.16 (m, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.40-7.47 (m, 2H), 7.64 (s,1H), 7.76-7.81 (m, 3H).

To a solution of Compound 52C (7.30 g, 32.02 mmol) in dry THF (80 mL)was added LiAlH₄ (1.20 g, 32.0 mmol) at 0° C. Then it was warmed to roomtemperature and stirred for 2 h. It was added with Na₂SO₄.10H₂O andfiltered to remove the solid. The filtrate was evaporated to giveCompound 52D (6.10 g, yield 100%) as a colorless oil. LC-MS (m/z): 187[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)1.95-2.02 (m, 2H), 2.88 (t, J=8.0 Hz, 2H), 3.72 (t, J=6.8 Hz, 2H), 7.33(d, J=7.2 Hz, 1H), 7.39-7.47 (m, 2H), 7.63 (s, 1H), 7.76-7.81 (m, 3H).

A mixture of Compound 52D (16 g, 86 mmol) in DCM (300 mL) was added DMP(43 g, 103 mmol) at room temperature. Then it was stirred at roomtemperature for 1 h. The mixture was diluted with EA (400 mL), filteredto remove solid, washed with water and brine, and purified by silica gelcolumn chromatography (ethyl acetate in petroleum ether, 20% v/v) toafford Compound 52E (14 g, yield 88%) as a colorless oil. LC-MS (m/z):185 [M+1]⁺.

A mixture of Compound 52E (8.00 g, 43.4 mmol) and 2NaO₅S₂ (8.3 g, 43.4mmol) in water/dioxane (100/20 mL) was stirred at room temperature for 2h. Then NaCN (4 g, 86.95 mmol) was added. The mixture was stirred atroom temperature overnight. It was diluted with ethyl acetate (200 mL),washed with water and brine, and purified by silica gel columnchromatography (ethyl acetate in petroleum ether, 50% v/v) to giveCompound 52F (6.6 g, yield 72%) as a colorless oil. LC-MS (m/z): 212[M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm)2.07-2.13 (m, 2H), 2.87-2.91 (m, 2H), 4.50-4.55 (m, 1H), 6.48-6.49 (d,J=4 Hz, 1H), 7.40-7.51 (m, 3H), 7.73 (s, 1H), 7.85-7.89 (m, 3H).

A solution of Compound 52F (6.6 g, 31.27 mmol) in MeOH (150 mL) wasbubbled with a gentle stream of HCl gas at room temperature for 6 h.Then it was quenched with H₂O (30 mL) and stirred at room temperaturefor 1 h. The mixture was diluted with ethyl acetate (300 mL), washedwith water and brine, dried with anhydrous Na₂SO₄, and evaporated togive Compound 52G (6.7 g, yield 87%) as colorless oil. LC-MS (m/z): 245[M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm)1.91-2.03 (m, 2H), 2.81-2.85 (t, J=8 Hz, 2H), 3.64 (s, 3H), 5.54-5.55(m, 1H), 7.37-7.39 (m, 1H), 7.42-7.50 (m, 2H), 7.69 (s, 1H), 7.83-7.87(t, J=8 Hz, 3H).

To a solution of Compound 52G (6.7 g, 27.46 mmol) in DCM (50 mL) wasadded DMP (14 g, 33 mmol). The mixture was stirred at room temperaturefor 2 h. Then it was diluted with ethyl acetate (150 mL), filtered toremove the solid, washed with water and brine, dried over anhydrousNa₂SO₄, and purified by silica gel column chromatography (ethyl acetatein petroleum ether, 30% v/v) to yield Compound 52H (5 g, yield 75%) as acolorless oil. LC-MS (m/z): 243 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.98-3.02 (t, J=8 Hz, 2H), 3.24-3.28 (t,J=8 Hz, 2H), 3.77 (s, 3H), 7.39-7.48 (m, 3H), 7.71 (s, 1H), 7.82-7.87(m, 3H).

To a solution of Compound 52H (2.0 g, 8.26 mmol) in DCM (50 mL) wasadded DAST (3 mL, 41.3 mmol) at room temperature. The mixture wasstirred at room temperature overnight. Then it was diluted with ethylacetate (150 mL), washed with saturated NaHCO₃, water and brine, andpurified by silica gel column chromatography (ethyl acetate in petroleumether, 40% v/v) to afford Compound 521 (2.0 g, yield 91%) as a whitesolid. LC-MS (m/z): 265 [M+1]⁺.

A mixture of Compound 521 (2.5 g, 4.47 mmol) and LiOH.H₂O (1.2 g, 28.4mmol) in THF/MeOH/H₂O (10/10/4 mL) was stirred at room temperature for 2h. Then it was adjusted to pH 6 with 1 M HCl aq solution. The mixturewas diluted with ethyl acetate (150 mL), washed with water and brine,dried with anhydrous Na₂SO₄, and purified by silica gel columnchromatography (ethyl acetate in petroleum ether, 30% v/v) to giveCompound 52J (1.8 g, yield 75%) as a white solid. LC-MS (m/z): 251[M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm)2.45-2.49 (m, 2H), 2.88-2.92 (m, 2H), 7.42-7.50 (m, 3H), 7.76 (s, 1H),7.84-7.88 (m, 3H).

A solution of Compound 11E (200 mg, 0.64 mmol), Compound 52J (241 mg,0.96 mmol), EDCI (183 mg, 0.96 mmol) and HOBt (130 mg, 0.96 mmol) in DCM(15 mL) was stirred at room temperature overnight. Then it was dilutedwith ethyl acetate (150 mL), washed with water and brine, and purifiedby prep-HPLC to afford Compound 52 (108 mg, yield 30%) as a white solid.LC-MS (m/z): 543 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristicpeaks: δ (ppm) 0.41-0.44 (m, 2H), 0.54-0.59 (m, 2H), 1.87-1.88 (m, 2H),2.01 (s, 2H), 2.16-2.27 (m, 2H), 2.49-2.71 (m, 2H), 3.10-3.15 (m, 2H),3.46-3.61 (m, 5H), 4.47-4.48 (m, 1H), 4.82 (s, 1H), 6.01-6.02 (m, 1H),7.24-7.34 (m, 3H), 7.38 (s, 1H), 7.45-7.51 (m, 2H), 7.65 (s, 1H),7.83-7.89 (m, 3H), 8.41-8.44 (m, 1H), 9.52 (s, 1H).

Example 53

To a solution of Compound A8 (500 mg, 1.1 mmol) in THF (20 mL) was added7-azabicyclo [2.2.1] heptane (1.1 g, 11 mmol) and stirred at 50° C. for16 h. The mixture was added water (50 mL) and extracted with ethylacetate (30 mL×3). The organic layer was washed with water (50 mL×3),brine (50 mL×1), dried over anhydrous Na₂SO₄, and concentrated to giveCompound 53A (600 mg, crude) as a colorless oil. LCMS: 439 [M+1]⁺.

A mixture of Compound 53A (660 mg, crude), LiOH.H₂O (150 mg) in EtOH (30mL) and H₂O (5 mL) was stirred at 100° C. for 16 h. The mixture wasconcentrated and added water (50 mL), and then extracted with DCM (30mL×3), dried over anhydrous Na₂SO₄, and concentrated to give Compound53B (400 mg, crude) as a colorless oil. LCMS: 305 [M+1]⁺.

To a solution of Compound 11E (250 mg), EDCI (290 mg), HOBt (200 mg,0.75 mmol) in DCM (10 mL) was added Compound 53B (400 mg, crude). Themixture was stirred at 25° C. for 24 h, added water (50 mL), extractedwith DCM (30 mL×3), dried over anhydrous Na₂SO₄, and purified byprep-HPLC to give Compound 53 (15 mg, yield 2%) as a colorless oil.LCMS: 533 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.69 (m, 4H), 2.14 (m, 4H), 3.35 (br, 1H), 3.47 (br, 1H), 4.11 (m,5H), 4.49 (br, 2H), 5.06 (s, 1H), 6.78 (m, 4H), 7.33 (m, 1H), 7.41 (m,1H), 7.58 (m, 1H), 8.10 (br, 1H), 10.58 (br, 1H).

Example 54

To a solution of Compound 54A (14.1 g, 19.4 mmol) in THF (15 mL) wasadded n-BuLi (8.1 mL, 19.4 mmol) carefully at −68° C. The mixture wasstirred at −68° C. for 15 min, and then Compound 8C (1.70 g, 6.48 mmol)in THF (10 mL) was added. The mixture was stirred at −68° C. for 15 minbefore quenched with saturated aq NH₄Cl. It was diluted with ethylacetate (100 mL), washed with water and brine, dried with anhydrousNa₂SO₄, and evaporated to give Compound 54B (1.90 g, yield 79%) as alight yellow oil. LC-MS (m/z): 396 [M+1]⁺.

A mixture of Compound 54B (1.90 g, 4.81 mmol) in THF (5 mL) andhydrochloric acid (6 M, 5 mL) was stirred at 20° C. overnight. It wasdiluted with ethyl acetate (200 mL), washed with water and brine,purified by silica gel chromatography eluted with MeOH in DCM (from 0%to 5%, v/v) to render Compound 54C (500 mg, yield 48%) as a colorlessoil. LC-MS (m/z): 356 [M+1]⁺.

To a solution of Compound 54C (520 mg, 1.46 mmol) in THF (50 mL) wasadded dropwise MsCl (184 mg, 161 mmol) at −40° C. The mixture wasstirred at −30° C. for 2 h. It was quenched with ice-water, diluted withethyl acetate (200 mL), washed with water and brine, dried withanhydrous Na₂SO₄, and evaporated to give Compound 54D (500 mg, yield79%) as a colorless oil. LC-MS (m/z): 434 [M+1]⁺.

A mixture of Compound 54D (500 mg, 1.15 mmol) and pyrrolidine (3 mL) inTHF (20 mL) was stirred at 50° C. overnight. It was evaporated to removeTHF. The residue was diluted with ethyl acetate (150 mL), washed withwater and brine, purified by silica gel chromatography (methanol indichloromethane, from 0% to 8% v/v) to yield Compound 54E (120 mg) as acolorless oil. LC-MS (m/z): 409 [M+1]⁺.

A mixture of Compound 54E (120 mg, 0.29 mmol) in EtOH/H₂O (10/2 mL) wasstirred at 85° C. overnight. It was diluted with ethyl acetate (150 mL),washed with water and brine, and purified by silica gel chromatography(methanol in dichloromethane, from 0% to 10% v/v) to give Compound 54F(90 mg, yield 100%) as a colorless oil. LC-MS (m/z): 275 [M+1]⁺.

The mixture of Compound 54F (90 mg, 0.33 mmol), EDCI (95 mg, 0.50 mmol),HOBt (68 mg, 0.50 mmol) and Compound 11E (81 mg, 0.33 mmol) in DCM (5mL) was stirred at 20° C. overnight. It was diluted with ethyl acetate(150 mL), washed with water and brine, and purified by prep-HPLC toafford Compound 54G (20 mg) as a white solid and Compound 54 (15 mg) asa white solid. For Compound 54G, LC-MS (m/z): 503 [M+1]⁺; ¹H-NMR (MeOD,400 MHz) major characteristic peaks: δ (ppm) 2.07 (s, 2H), 2.21 (s, 2H),3.13-3.26 (m, 2H), 3.52-3.58 (m, 1H), 3.77-3.89 (m, 3H), 3.91 (s, 3H),4.61-4.67 (m, 1H), 4.82 (d, J=5.2 Hz, 1H), 6.34 (s, 1H), 7.21-7.27 (m,2H), 7.35-7.38 (m, 2H), 7.47 (s, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.87 (s,1H). For Compound 54, LC-MS (m/z): 503 [M+1]⁺; ¹H-NMR (MeOD, 400 MHz)major characteristic peaks: δ (ppm) 2.05 (s, 2H), 2.20 (s, 2H),3.17-3.26 (m, 2H), 3.64-3.82 (m, 4H), 3.85 (s, 3H), 4.80 (d, J=5.2 Hz,1H), 5.16 (s, 1H), 6.34 (s, 1H), 7.18-7.21 (m, 1H), 7.32-7.34 (m, 1H),7.38-7.40 (m, 2H), 7.55-7.60 (m, 2H), 7.91 (s, 1H).

Example 55

A solution of Compound 55A (100 mg, 0.2 mmol), hydroxylaminehydrochloride (41 mg, 0.6 mmol) in MeOH (5 mL) was stirred at 25° C. for16 h. The mixture was diluted with saturation aq NaHCO₃ (15 mL) andextracted with EtOAc (15 mL×3). The combined organic layers were washedwith brine (15 mL), dried over Na₂SO₄, and concentrated to give a crudeproduct. The crude product was purified by prep-HPLC to give atrifluoroacetic acid salt of Compound 55 (1.6 mg, yield 1.3%) as a whitesolid. LC-MS (m/z): 520 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.82 (s, 4H), 2.00-2.22 (m, 2H), 2.65-2.75(m, 3H), 2.92-2.97 (m, 1H), 4.18-4.24 (m, 4H), 5.33-5.47 (m, 2H),6.82-6.84 (m, 1H), 6.95 (s, 1H), 7.13-7.14 (m, 2H), 7.33-7.34 (m, 1H),7.40-7.43 (m, 1H), 7.54-7.55 (m, 1H).

Example 56

To a solution of 5-bromo-2-methoxypyridine (10 g, 53.2 mmol) in THF (200mL) was added n-BuLi (2.5 M, 22 mL) at −60° C. under N₂. It was stirredfor 0.5 h, and then a solution of Compound A4 (7.02 g, 17.7 mmol) in THF(50 mL) was added. The reaction mixture was stirred at −60° C. for anadditional 1 h, before quenched with saturate aq NH₄Cl solution. It wasextracted with ethyl acetate (100 mL×2), brine (100 mL), and dried overNa₂SO₄. The crude product was purified by column chromatography onsilica gel (ethyl acetate in petroleum, 10% v/v) to give Compound 56A(7.5 g, yield 95%) as a colorless liquid. LC-MS (m/z): 445[M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) −0.13 (s, 3H),−0.11 (s, 3H), 0.75 (s, 9H), 3.88-3.92 (m, 1H), 3.99-4.00 (m, 1H), 4.02(s, 3H), 5.14 (s, 2H), 5.29 (t, J=3.6 Hz, 1H), 5.93 (d, J=6.8 Hz, 1H),6.81 (d, J=8.8 Hz, 1H), 7.37-7.38 (m, 5H), 8.13 (dd, J=2.0, 8.8 Hz, 1H),8.80 (d, J=2.0 Hz, 1H).

Compound 56A (7.5 g, 16.9 mmol) was dissolved in anhydrous THF (500 mL)and cooled down −80° C. under nitrogen atmosphere. L-Selectride (33.8mL, 1M solution in THF, 33.8 mmol) was added dropwise to the solutionwhile keeping the temperature at −80° C. The reaction was stirred at−80° C. for 0.5 h before quenched with saturate aq NH₄Cl solution. Itwas extracted with ethyl acetate (100 mL×3). The combined organic phaseswere washed water and brine, and dried over Na₂SO₄. The crude productwas purified by column chromatography on silica gel (ethyl acetate inpetroleum, 20% v/v) to give Compound 56B (5.1 g, yield 68%) as acolorless oil. LC-MS (m/z): 447 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) −0.08 (s, 6H), 0.92 (s, 9H), 3.68 (m, 1H),3.84 (m, 3H), 3.94 (s, 3H), 5.05 (m, 3H), 5.46 (d, J=7.6 Hz, 1H), 6.71(d, J=8.4 Hz, 1H), 7.32-7.34 (m, 5H), 7.59 (d, J=8.4 Hz, 1H), 8.14 (s,1H).

To a solution of Compound 56B (5.1 g, 11.4 mmol) in THF (120 mL) wasadded a solution of TBAF (1.49 g, 5.7 mmol) in THF (10 mL) at 0° C. Themixture was stirred at 25° C. overnight, and then evaporated to reducethe volume, added water (50 mL), extracted with ethyl acetate (100mL×3), washed with brine, and dried over Na₂SO₄. The crude product waspurified by column chromatography on silica gel (methanol indichloromethane, 5% v/v) to give Compound 56C (3.42 g, yield 52%) as acolorless oil. LC-MS (m/z): 333 [M+1]⁺.

To a solution of Compound 56C (3.42 g, 8.58 mmol) in THF (100 mL) wasadded Et₃N (3.12 g, 30.9 mmol). The mixture was cooled to −40° C., andthen MsCl (1.30 g, 11.3 mmol) was added slowly. It was stirred at −40°C. about half an hour before added pyrrolidine (3.78 g, 53.2 mmol). Thereaction mixture was allowed to warm up to rt and then heated to 50° C.Stirred overnight, the mixture was added water (50 mL), extracted withethyl acetate (50 mL×3), washed with brine (100 mL), and dried overNa₂SO₄. The crude product was purified by column chromatography onsilica gel (methanol in dichloromethane, 3% v/v) and flash column(reverse-phase, 0.05% NH₄OH/MeOH, v/v) to give Compound 56D (800 mg,yield 39%) as white syrup. LC-MS (m/z): 386 [M+1]⁺.

To a solution of Compound 56D (400 mg, 1.04 mmol) in methanol (10 mL)was added Pd(OH)₂ (40 mg). The mixture was stirred at 25° C. under H₂overnight. It was filtered and evaporated to give Compound 56E (260 mg,crude). LC-MS (m/z): 252 [M+1]⁺.

To a solution of Compound 56E (260 mg, 1.04 mmol) and Compound 11E (255mg, 1.04 mmol) in DCM (10 mL) was added EDCI (298 mg, 1.55 mmol) andHOBt (210 mg, 1.55 mmol) under N₂. The mixture was stirred at 25° C.overnight. TLC showed the starting material was consumed completely;water was added to the mixture and then extracted with DCM (50 mL×3).The combined organic layers were washed with brine, dried over sodiumsulfate, and concentrated to give a crude product. The crude product waspurified by prep-HPLC to give Compound 56 (98.6 mg, yield 19%) as awhite solid. LC-MS (m/z): 480 [M+1]⁺, ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks δ (ppm): 2.10 (s, 4H), 3.03 (s, 2H), 3.58-3.72 (m,4H), 3.86 (s, 3H), 4.26 (s, 1H), 5.24 (m, 1H), 6.71 (s, 1H), 6.84 (s,1H), 7.33 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.86(s, 1H), 8.38 (m, 2H), 11.43 (s, 1H).

Example 57

To a solution of Compound 55A was dissolved in CD₃OD (5 mL) was addedNaBD₄ (13 mg, 0.32 mmol) at −30° C. under nitrogen atmosphere. Thereaction was warmed to 0° C. and kept stirring for 1 h. After quenchedwith 2% CD₃COOD in D20, the mixture was extracted with dichloromethane(50 mL×3) and washed with D20. The crude product was purified byprep-HPLC to give Compound 57 (20 mg, yield 25%) as a white solid. LC-MS(m/z): 508 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 2.13 (s, 4H), 3.01 (s, 2H), 3.49 (s, 2H), 3.81 (s, 2H), 4.12-4.17(m, 4H), 4.47-4.49 (m, 1H), 6.76 (m, 2H), 6.84 (s, 1H), 7.35 (dd, J=2.0,8.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.90 (d, J=2.0 Hz,1H), 11.95 (s, 1H).

Example 58

A solution of Compound 45A (62 mg, 0.12 mmol) in DMF (2 mL) was addedNaN₃ (24 mg, 0.36 mmol) and the mixture was stirred at 50° C. for 3 h.The mixture was added H₂O (mL) and extracted with ethyl acetate (50mL×3). The combined organic layer was washed with brine, andconcentrated to give Compound 58A (40 mg, yield 63%) as a white solid.LC-MS (m/z): 532 [M+1]⁺.

To a solution of Compound 58A (40 mg, 0.075 mmol) in THF (1 mL) wasadded PPh₃ (21 mg, 0.08 mmol), the mixture was stirred at 20° C. for 18h. It was added H₂O (mL) and stirred for 2 h and concentrated. The crudeproduct was purified by prep-HPLC to give Compound 58 (5 mg, yield 13%)as a white solid. LC-MS (m/z): 506 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.79-1.81 (m, 4H), 2.40-2.45 (m, 1H),2.56-2.64 (m, 6H), 3.34-3.38 (m, 1H), 4.14-4.34 (m, 5H), 4.90-4.91 (m,2H), 6.75-6.84 (m, 3H), 7.07 (s, 1H), 7.32-7.35 (m, 1H), 7.45-7.58 (m,1H), 7.59 (s, 1H), 9.66-9.67 (m, 1H).

Example 59

To a solution of Compound 59A (10 g, 50 mmol) and K₂CO₃ (20.7 g, 150mmol) in DMF (30 mL) was added MeI (21.3 g, 150 mmol), and the mixturewas stirred for 15 h at 25° C. After the TLC showed completedisappearance of the starting material, the reaction was quenched byadding water. It was extracted with ethyl acetate. The extracts wereevaporated to dryness to give Compound 59B (10.6 g, yield 98%) as ayellow solid. LC-MS (m/z): 215 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.92 (s, 3H), 6.90 (d, J=8.8 Hz, 1H), 7.63(dd, J=8.8, 2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 10.39 (s, 1H).

To a solution of Compound 59B (9 g, 42 mmol) in DCM (90 mL) was addedDAST (33.7 g, 209 mmol), and the mixture was stirred for 18 h at 25° C.The mixture was adjusted to pH 8 with saturated NaHCO₃, extracted withDCM, and dried over anhydrous Na₂SO₄. After evaporation, the crudeproduct was purified by column chromatography on silica gel (ethylacetate in petroleum ether, 3% v/v) to get Compound 59C (5.14 g, yield52%) as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 3.85 (s, 3H), 6.82 (d, J=9.2 Hz, 1H), 6.89 (t,J_(F-H)=552 Hz, 1H), 7.52 (dt, J=8.8, 1.2 Hz, 1H), 7.66 (t, J=1.2 Hz,1H).

To a solution of Compound 59C (5 g, 21 mmol) in THF (100 mL) was addedn-BuLi (2.4 M, 8.75 mL) at −60° C. under N₂. After stirred for 0.5 h, asolution of Compound A4 (2.77 g, 7 mmol) in THF (50 mL) was addedslowly. The mixture was stirred at −60° C. for 1 h, before quenched withsaturated aq NH₄Cl solution. It was extracted with ethyl acetate, washedwith brine (100 mL) and dried over Na₂SO₄. The crude product waspurified by column chromatography on silica gel (ethyl acetate inpetroleum, 20% v/v) to give Compound 59D (2.65 g, yield 76%) as a yellowoil. LC-MS (m/z): 494 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) −0.15 (s, 3H), −0.12 (s, 3H), 0.74 (s,9H), 3.85-3.92 (m, 2H), 3.96 (s, 3H), 5.13 (s, 2H), 5.33-5.38 (m, 1H),5.93 (d, J=7.6 Hz, 1H), 6.79-7.06 (m, 2H), 7.31-7.37 (m, 5H), 8.10 (d,J=8.4 Hz, 1H), 8.18 (s, 1H).

Compound 59D (2.65 g, 5.36 mmol) was dissolved in THF (100 mL) andcooled to −70° C. under nitrogen atmosphere. L-Selectride (1M solutionin THF, 10.7 mL) was added dropwise while keeping the temperature at−70° C. After an hour, the reaction was quenched with saturated aq NH₄Clsolution and the mixture was extracted with ethyl acetate, and driedover Na₂SO₄. The crude product was purified by column chromatography onsilica gel (ethyl acetate in petroleum, 20% v/v) to give Compound 59E(2.1 g, yield 79%) as a colorless oil. LC-MS (ESI) m/z: 478 [M−17]⁺.

To a solution of Compound 59E (2.1 g, 4.23 mmol) in THF (50 mL) wasadded a solution of TBAF (555 mg, 2.12 mmol) in THF (5 mL) at 0° C. Themixture was stirred at rt for 18 h, condensed, added water, andextracted with ethyl acetate. The combined organic layers were washedwith brine and dried over Na₂SO₄. The crude product was purified byflash column chromatography on silica gel (MeOH in H₂O, 40% v/v) to giveCompound 59F (760 mg, yield 47%) as a colorless oil. LC-MS (m/z): 364[M−17]⁺.

To a solution of Compound 59F (0.76 g, 2 mmol) in THF (50 mL) was addedEt₃N (0.6 g, 6 mmol) at −40° C. MsCl (241 mg, 2.09 mmol) was addedslowly and the mixture was stirred at −20° C. for 7 h. Pyrrolidine (1.13g, 16 mmol) were added and the reaction mixture was allowed to warm upto rt and then heated to 50° C. for 15 h. The crude product was purifiedby column chromatography silica gel (methanol in dichloromethane, 5%v/v) to give Compound 59G (270 mg, yield 31%) as colorless oil. LC-MS(m/z): 435 [M+1]⁺.

To a solution of Compound 59G (270 mg, 0.62 mmol) in methanol (20 mL)was added Pd(OH)₂ (27 mg) and the mixture was stirred at 25° C. under H₂for 24 h. The mixture was filtered and evaporated to render Compound 59H(260 mg, yield 98%) as a white solid. LC-MS (m/z): 301 [M+1]⁺.

The mixture of Compound 59H (180 mg, 0.6 mmol), EDCI (173 mg, 0.9 mmol),HOBt (122 mg, 0.9 mmol) and Compound 11E (178 mg, 0.72 mmol) in DCM (15mL) was stirred for 16 h at 25° C. The mixture was washed with saturatedaq NaHCO₃ and brine. After evaporation, the residues were purified byprep-HPLC to afford Compound 591 (64 mg, yield 11%) as the white solidand Compound 59 (59 mg, yield 10%) as the white solid. For Compound 591,LC-MS (m/z): 529 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 2.07-2.19 (m, 4H), 2.77-2.91 (m, 2H), 3.21-3.24 (m, 1H),3.63-3.64 (m, 1H), 3.76 (s, 3H), 3.80-3.82 (m, 1H), 3.88-3.90 (m, 1H),4.52 (s, 1H), 5.02 (s, 1H), 6.72-7.00 (m, 3H), 7.31-7.34 (m, 1H),7.40-7.42 (m, 2H), 7.52-7.62 (m, 2H), 9.15 (d, J=4.8 Hz, 1H), 11.78 (s,1H). For Compound 59, LC-MS (m/z): 529 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 2.13 (s, 4H), 2.88-3.04 (m, 2H),3.53-3.63 (m, 2H), 3.71 (s, 3H), 3.74-3.81 (m, 2H), 4.60 (s, 1H), 5.19(s, 1H), 6.65-6.98 (m, 3H), 7.32-7.39 (m, 3H), 7.51-7.53 (m, 2H), 7.95(d, J=6.4 Hz, 1H), 11.69 (s, 1H).

Example 60

A solution of Compound 60A (21 mg, 0.1 mmol) and K₂CO₃ (55 mg, 0.4 mmol)in D20 (3 mL) was stirred at 110° C. for 16 h under N₂. The mixture wasacidified by the addition of 1M HCl solution, extracted with DCM (20mL×2), dried over anhydrous Na₂SO₄, and concentrated to yield Compound60B (15 mg, yield 71%) as a white solid. LC-MS (m/z): 167 [M−45]⁻;¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 6.63 (s,1H), 7.21 (m, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H).

A mixture of Compound 60B (100 mg, 0.47 mmol) in SOCl₂ (3 mL) wasstirred at 25° C. for 2 h. The mixture was concentrated to give Compound60C (100 mg, crude) as a yellow oil which was used for the next stepwithout further purification.

Intermediate A was dissolved in CD₃OD and the solvent evaporated. To asolution of Intermediate A (100 mg, 0.36 mmol) in DCM (3 mL) was addedCompound 60C solution (100 mg, 0.43 mmol). The mixture was stirred at25° C. for 0.5 h. The mixture was added water (30 mL), extracted withDCM (30 mL×3), dried over anhydrous Na₂SO₄, and purified by prep-HPLC togive Compound 60 (19 mg, yield 9%) as a white foam. LC-MS (m/z): 473[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.03(m, 4H), 2.82 (m, 2H), 3.16 (m, 1H), 3.48 (m, 1H), 3.73 (br, 2H), 4.14(m, 4H), 4.45 (m, 1H), 4.84 (d, J=2.4 Hz, 1H), 6.41 (s, 1H), 6.64 (s,2H), 6.76 (s, 1H), 7.18 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.45 (d, J=2.0Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 11.42 (br, 1H).

Example 61

To a solution of Compound A6 (1 g, 2 mmol) in CH₃CN (15 mL) was addedNBS (564 mg, 3.2 mmol) and the mixture was stirred at 50° C. for 1.5 h.It was cooled to rt, diluted with DCM (50 mL), washed with water (100mL×3) and brine (100 mL), dried over Na₂SO₄, and concentrated to giveCompound 61A (1.2 g, crude) as a yellow solid. LC-MS (m/z): 534 [M-18]⁺.

To a solution of Compound 61A (1 g, 2.1 mmol) in THF (20 mL) was addedTBAF (275 mg, 1.05 mmol) at 0° C. The mixture was stirred at rtovernight, evaporated to remove solvent, and added water (50 mL). It wasextracted with ethyl acetate (50 mL×2), washed with brine (100 mL),dried over Na₂SO₄, concentrated and, purified by column chromatographyon silica gel (33% ethyl acetate in petroleum) to give Compound 61B (720mg, yield 80%) as a white solid. LC-MS (m/z): 420 [M−18]⁺.

To a solution of Compound 61B (720 mg, 1.6 mmol) in THF (20 mL) wasadded Et₃N (500 mg, 4.94 mmol). The mixture was cooled to −15° C., addedMsCl (207 mg, 1.8 mmol) slowly, and stirred at −15° C. for half an hour.It was diluted with water, extracted with ethyl acetate (50 mL×2),washed with brine (50 mL), dried over Na₂SO₄, and concentrated to renderCompound 61C (700 mg, yield 83%), which was used for the next stepwithout further purification. LC-MS (m/z): 498 [M−18]⁺.

To a solution of Compound 61C (700 mg, 1.36 mmol) in THF (20 mL) wasadded and pyrrolidine (1 g, 13.6 mmol). The reaction mixture was allowedto warm up to rt and then heated at 50° C. overnight. After cooled to rtand added water (20 mL), the mixture was extracted with ethyl acetate(50 mL×2), washed with water (50 ml×3) and brine (50 mL), dried overNa₂SO₄, and concentrated to give Compound 61D (600 mg, crude). LC-MS(m/z): 491 [M+1]⁺.

To a solution of Compound 61D (600 mg, 1.22 mmol) in EtOH (20 mL) andH₂O (2 mL) was added LiOH (154 mg, 3.67 mmol) and then the mixture wasstirred at 100° C. overnight. After cooled to rt and added water (50mL), the mixture was extracted with DCM (50 mL×2), washed with brine (50mL), dried over Na₂SO₄, and concentrated to yield Compound 61E (200 mg,yield 50%) as a yellow liquid. LC-MS (m/z): 357 [M+1]⁺.

A mixture of Compound 11E (166 mg, 0.67 mmol), EDCI (216 mg, 1.12 mmol),HOBt (216 mg, 1.12 mmol), and Compound 61E (200 mg, 0.56 mmol) in DCM(20 mL) was stirred at rt overnight. The mixture was added water,extracted with DCM (50 mL×2), washed with brine (50 mL), dried overNa₂SO₄, and concentrated. The crude product was purified by prep-HPLC togive Compound 61 (130 mg, yield 40%) as a white solid. LC-MS (m/z): 585[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 2.15(s, 4H), 2.95 (s, 1H), 3.10 (s, 1H), 2.57 (m, 2H), 3.87 (m, 2H), 3.94(m, 2H), 4.04 (m, 1H), 4.13 (m, 1H), 4.68 (d, J=7.2 Hz, 1H), 5.31 (s,1H), 6.79 (s, 1H), 7.01 (s, 1H), 7.08 (s, 1H), 7.33 (m, 1H), 7.44 (d,J=8.8 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 11.79 (s,1H).

Example 62

To a solution of Compound A8 (437 mg, 1 mmol) in CH₃CN (20 mL) was added3,3-dimethylazetidine (363 mg, 3 mmol), K₂CO₃ (414 mg, 3 mmol), and NaI(449 mg, 3 mmol). The mixture was heated at 82° C. overnight. It wascooled to rt, filtered and concentrated in vacuum to give a crudeCompound 62A (426 mg, crude) as a yellow oil. LC-MS (m/z): 427 [M+1]⁺.

To a solution of Compound 62A (426 mg, 1 mmol) in EtOH/water (20 mL,9:1, v/v) was added LiOH.H₂O (420 mg, 10 mmol). The mixture was refluxedfor 36 h. It was added water (20 mL) and extracted with ethyl acetate(20 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuum to yield Compound 62B (300 mg, crude) as ayellow oil. LC-MS (m/z): 293 [M+1]⁺.

To a mixture of Compound 62B (292 mg, 1 mmol) in DCM (20 mL) was addedEDCI (288 mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol) and Compound 11E (246mg, 1 mmol). It was stirred at 25° C. overnight, added water (10 mL),extracted with DCM (20 mL×3), dried over anhydrous Na₂SO₄, and purifiedby prep-HPLC to afford a trifluoroacetic acid salt of Compound 62 (139mg, yield 27%) as a white solid. LC-MS (m/z): 521 [M+1]⁺; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 1.30 (s, 3H), 1.43 (s, 3H),3.50 (s, 2H), 3.64 (t, J=12 Hz, 2H), 4.05-4.19 (m, 6H), 4.30 (s, 1H),5.01 (s, 1H), 6.73 (s, 3H), 6.8 (s, 1H), 7.34 (d, J=8 Hz, 1H), 7.42 (d,J=8 Hz, 1H), 7.58 (s, 1H), 7.89 (d, J=8 Hz, 1H), 12.23 (s, 1H).

Example 63

To a solution of Compound 63A (3.00 g, 12.50 mmol) in DCM (100 mL) wasadded DMP (6.36 g, 15.00 mmol) carefully. The mixture was stirred at 25°C. overnight. The mixture was quenched with aq Na₂S₂O₃ solution, dilutedwith ethyl acetate (200 mL), washed with water and brine, and purifiedwith silica gel column chromatography (ethyl acetate in petroleum ether,from 0% to 20% v/v) to render Compound 63B (2.10 g, yield 70%) as awhite solid. LC-MS (m/z): 239 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 3.06-3.11 (m, 3H), 3.15-3.30 (m, 1H), 3.84(s, 3H), 3.90-3.93 (m, 0.5H), 4.06-4.10 (m, 0.5H), 7.10-7.20 (m, 3H).

To a solution of Compound 63B (200 mg, 1.26 mmol), in DCM (5 mL) wasadded DAST (1.01 g, 6.30 mmol) dropwise at 20° C. The mixture wasstirred at 20° C. overnight. The mixture was diluted with ethyl acetate(100 mL), washed with water and brine, and purified by silica gel columnchromatography (dichloromethane in petroleum ether, from 0% to 8% v/v)to yield Compound 63C (280 mg, yield 85%) as a colorless oil. LC-MS(m/z): 261 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 3.06-3.11 (m, 3H), 3.15-3.30 (m, 1H), 3.84 (s, 3H), 3.90-3.93 (m,0.5H), 4.06-4.10 (m, 0.5H), 7.10-7.20 (m, 3H).

A mixture of Compound 63C (280 mg, 1.08 mmol) and LiOH.H₂O (136 mg, 3.24mmol) in THF/MeOH/H₂O (10/10/5 mL) was stirred at 20° C. overnight. Themixture was acidified to pH 2 with dilute HCl and extracted with DCM.Then organic phase washed with water and brine, dried over anhydrousNa₂SO₄, and evaporated to give Compound 63D (230 mg, yield 86%) as whitesolid. LC-MS (m/z): 465 [M−1]⁻.

A mixture of Compound 63D (89 mg, 0.36 mmol), Compound 11E (100 mg, 0.36mmol), EDCI (104 mg, 0.54 mmol) and HOBt (73 mg, 0.54 mmol) in DCM (10mL) was stirred at 25° C. overnight. The mixture was diluted with ethylacetate (150 mL), washed with water and brine, and purified by prep-HPLCto afford Compound 63 (100 mg, yield 55%) as a white solid. LC-MS (m/z):507 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ(ppm) 1.88 (br s, 2H), 2.01 (br s, 2H), 2.50-2.83 (m, 4H), 3.00-3.16 (m,3H), 3.50-3.55 (m, 5H), 4.13-4.20 (m, 4H), 4.42-4.50 (m, 1H), 4.74 (brs, 1H), 5.88 (s, 1H), 6.78-6.84 (m, 3H), 7.20-7.26 (m, 3H), 8.40 (d,J=8.8 Hz, 1H), 9.50 (s, 1H).

Example 64

To a solution of Intermediate C (292 mg, 1 mmol) in DCM (20 mL) wasadded EDCI (288 mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol) and Compound 11E(246 mg, 1 mmol) and it was stirred at 25° C. overnight. The mixture wasadded water (10 mL), extracted with dichloromethane (20 mL×3), driedover anhydrous Na₂SO₄, and purified by prep-HPLC to afford atrifluoroacetic acid salt of Compound 64 (120 mg, yield 19%) as a whitesolid. LC-MS (m/z): 525 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.14 (s, 4H), 2.91-3.03 (m, 2H), 3.50 (d,J=4 Hz, 2H), 3.82 (s, 2H), 4.11-4.19 (m, 4H), 4.44 (d, J=4 Hz, 1H), 5.07(s, 1H), 6.61 (s, 1H), 6.70 (d, J=12 Hz, 1H), 6.86 (s, 1H), 7.34 (d,J=12 Hz, 1H), 7.43 (d, J=12 Hz, 1H), 7.58 (s, 1H), 7.80 (d, J=8 Hz, 1H),11.76 (s, 1H).

Example 65

To a solution of Intermediate D (250 mg, 0.8 mmol) in dichloromethane(20 mL) was added EDCI (230 mg, 1.2 mmol), HOBt (162 mg, 1.2 mmol) andCompound 11E (196 mg, 0.8 mmol). The mixture was stirred at 25° C.overnight, added water (10 mL), extracted with dichloromethane (20mL×3), dried over anhydrous Na₂SO₄, and purified by prep-HPLC to afforda trifluoroacetic acid salt of Compound 65 (75 mg, yield 14%) as a whitesolid. LC-MS (m/z): 541[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.13 (s, 4H), 3.01 (s, 2H), 3.51 (s, 2H),3.80 (s, 2H), 4.06 (s, 2H), 4.20 (s, 2H), 4.47 (d, J=4 Hz, 1H), 5.06 (s,1H), 6.74 (s, 1H), 6.80 (s, 1H), 6.94 (s, 1H), 7.34 (d, J=12 Hz, 1H),7.43 (d, J=12 Hz, 1H), 7.58 (s, 1H), 7.80 (d, J=8 Hz, 1H), 11.76 (s,1H).

Example 66

To a solution of Compound A8 (437 mg, 1 mmol) in CH₃CN (20 mL) was added3-methylazetidine hydrochloride (321 mg, 3 mmol), K₂CO₃ (414 mg, 3 mmol)and NaI (449 mg, 3 mmol). The mixture was heated at 82° C. overnight. Itwas cooled to rt, filtered, and concentrated in vacuum to give crudeCompound 66A (426 mg, crude) as a yellow oil. LC-MS (m/z): 413 [M+1]⁺.

To a solution of Compound 66A (412 mg, 1 mmol) in EtOH/water (20 mL,9:1, v/v) was added LiOH.H₂O (420 mg, 10 mmol). The mixture was refluxedfor 24 h and water (20 mL) was added. It was extracted with ethylacetate (20 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuum to give crude Compound 66B (280 mg,crude) as a yellow oil. LC-MS (m/z): 278 [M+1]⁺.

To a mixture of Compound 66B (140 mg, 0.5 mmol) in DCM (10 mL) was addedEDCI (144 mg, 0.75 mmol), HOBt (100 mg, 0.75 mmol), and Compound 11E(123 mg, 0.5 mmol) and stirred at 30° C. overnight. It was added water(10 mL), extracted with DCM (20 mL×3), dried over anhydrous Na₂SO₄, andpurified by prep-HPLC to give a trifluoroacetic acid salt of Compound 66(20 mg, yield 6%) as a white solid. LC-MS (m/z): 507 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.23-1.38 (m, 3H),2.92 (s, 1H), 3.15 (s, 1H), 3.49 (s, 3H), 4.01-4.15 (m, 5H), 4.30 (s,1H), 4.43 (s, 1H), 5.00 (s, 1H), 6.73 (s, 3H), 6.80 (s, 1H), 7.34 (d,J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.58 (s, 1H), 7.85 (s, 1H), 12.34 (s,1H).

Example 67

A mixture of Compound 11E (100 mg, 0.41 mmol), EDCI.HCl (118 mg, 0.62mmol), HOBt (81 mg, 0.62 mmol), Compound 44G (126 mg, 0.41 mmol) in DCM(5 mL) was stirred at 28° C. overnight. The mixture was added dropwisesat. aq NaHCO₃, and then extracted with DCM (50 mL×2), washed with brine(50 mL×1), dried over Na₂SO₄, and concentrated. The crude product waspurified by prep-HPLC to give Compound 67 (62 mg, yield 28%) as a whitesolid. LC-MS: 539 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristicpeaks: δ (ppm) 0.62 (m, 2H), 081 (m, 2H), 1.88 (m, 2H), 2.03 (m, 2H),2.60-2.65 (m, 2H), 2.76-2.80 (m, 2H), 3.06-3.20 (m, 3H), 3.41-3.54 (m,4H), 3.88 (s, 1H), 5.53 (s, 1H), 8.84 (s, 1H), 6.00 (s, 1H), 7.15-7.21(m, 3H), 7.27-7.31 (m, 1H), 7.36-7.40 (m, 2H), 8.45 (d, J=9.2 Hz, 1H).

Example 68

To a solution of Compound 11B (4.59 g, 30 mmol) in THF (125 mL) wasadded n-BuLi (2.4 M, 12.5 mL) at −60° C. under N₂ and stirred for 0.5 hand then a solution of Compound A4 (3.97 g, 10 mmol) in THF (50 mL) wasadded slowly. The mixture was stirred at −60° C. for 1 h, beforequenched by addition of saturate aq NH₄Cl solution The mixture wasextracted with ethyl acetate, brine, and dried over Na₂SO₄. The crudeproduct was purified by column chromatography on silica gel (ethylacetate in petroleum, 5% v/v) to give Compound 68A (3.48 g, yield 71%)as a yellow oil. LC-MS (m/z): 488 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) −0.11 (s, 3H), −0.08 (s, 3H), 0.75 (s,9H), 4.99 (dd, J=4.4, 10.0 Hz, 1H), 4.19 (dd, J=3.6, 10.0 Hz, 1H), 5.14(s, 2H), 5.26-5.30 (m, 1H), 5.87 (d, J=7.6 Hz, 1H), 7.32-7.38 (m, 5H),7.45-7.57 (m, 3H), 7.70 (d, J=2.0 Hz, 1H).

A solution of Compound 68A (3.48 g, 7.14 mmol) in THF (200 mL) was addedL-selectride (1M solution in THF, 14.3 mL) dropwise at −70° C. undernitrogen atmosphere. After stirred for one hour, the reaction wasquenched with saturated aq NH₄Cl solution and the mixture was extractedwith ethyl acetate and dried over Na₂SO₄. The crude product was purifiedby column chromatography on silica gel (ethyl acetate in petroleum, 20%v/v) to give Compound 68B (3.41 g, yield 97%) as a colorless oil. LC-MS(m/z): 472 [M−17]⁺.

To a solution of Compound 68B (3.41 g, 6.95 mmol) in THF (100 mL) wasadded a solution of TBAF (0.91 mg, 3.48 mmol) in THF (10 mL) at 0° C.After stirred at rt for 18 h, the mixture was evaporated to removesolvent. The residue was taken up with water, extracted with ethylacetate, washed with brine, and dried over Na₂SO₄. The crude waspurified by flash column chromatography on silica gel (MeOH in DCM, 5%v/v) to render Compound 69C (2.01 g, yield 76%) as a white solid. LC-MS(m/z): 358 [M−17]⁺.

To a solution of Compound 68C (2.01 g, 5.35 mmol) in THF (100 mL) wasadded Et₃N (1.62 g, 16.01 mmol) at −40° C. MsCl (646 mg, 5.62 mmol) wasadded slowly and the mixture was stirred at −20° C. for 4 h. Afterevaporation, Compound 68D (2.28 g, yield 100%) was obtained as yellowoil, which was used for the next step without purification.

To a solution of Compound 68D (2.28 g, 5.35 mmol) in THF (100 mL) wasadded pyrrolidine (3.03 g, 42.8 mmol). The reaction mixture was heatedat 50° C. for 15 h. After evaporation, the crude product was purified bycolumn chromatography on silica gel (methanol in dichloromethane, 5%v/v) to give Compound 68E (940 mg) as a colorless oil. LC-MS (m/z): 429[M+H]⁺.

To a solution of Compound 68E (310 mg, 0.72 mmol) in ethanol (10 mL) andH₂O (10 mL) was added LiOH (152 mg, 3.61 mmol). The mixture was refluxedfor 4 h. After evaporation, the mixture was extracted by DCM, and washedby brine, and dried over anhydrous Na₂SO₄. After filtration andevaporation, Compound 69F (210 mg, yield 98%) was obtained as a yellowoil. LC-MS (m/z): 295 [M+1]⁺.

A mixture of Compound 68F (210 mg, 0.71 mmol), EDCI (204 mg, 1.07 mmol),HOBt (145 mg, 1.07 mmol) and Compound 11E (210 mg, 0.85 mmol) in DCM (10mL) was stirred at 25° C. for 16 h. The mixture was washed by saturatedNaHCO₃ and brine. After evaporation, the crude was purified by prep-HPLCand followed by chiral-prep-HPLC to afford Compound 68G (77 mg, yield17%) as a white solid and Compound 68 (82 mg, yield 18%) as a whitesolid. For Compound 68G, LCMS (m/z): 523 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 2.07 (s, 4H), 2.82-2.91 (m, 2H),3.26-3.29 (m, 1H), 3.70-3.95 (m, 3H), 4.82 (s, 1H), 5.02 (d, J=4.0 Hz,1H), 6.68 (s, 1H), 6.91 (s, 1H), 7.19-7.21 (m, 1H), 7.28-7.33 (m, 3H),7.35 (d, J=2.0 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 9.18 (d, J=7.2 Hz, 1H),11.70 (s, 1H). For Compound 68, LC-MS (m/z): 523 [M+1]⁺; ¹H-NMR (CDCl₃,400 MHz) major characteristic peaks: δ (ppm) 2.13 (s, 4H), 2.94-3.06 (m,2H), 3.61 (s, 2H), 3.85 (s, 2H), 4.81 (d, J=6.0 Hz, 1H), 5.33 (s, 1H),6.64 (s, 2H), 7.06-7.09 (m, 1H), 7.14-7.15 (m, 1H), 7.19-7.21 (m, 1H),7.28-7.31 (m, 2H), 7.39-7.40 (m, 1H), 7.96 (d, J=7.2 Hz, 1H), 11.78 (s,1H).

Example 69

A mixture of Compound 33F (150 mg, 0.54 mmol), EDCI.HCl (154 mg, 0.81mmol), HOBt (109 mg, 0.81 mmol), Compound 44G (166 mg, 0.54 mmol) in DCM(5 mL) was stirred at 28° C. overnight. The reaction was quenched withaddition of sat. aq NaHCO₃ and the mixture was extracted with DCM (50mL×2), washed with brine (50 mL×1), dried over Na₂SO₄, and concentrated.The crude product was purified by prep-HPLC to give Compound 70 (42 mg,yield 14.1%) as a white solid and Compound 69A (42 mg, yield 14.1%) as awhite solid. For Compound 69, LC-MS (m/z): 573 [M+1]⁺; ¹H-NMR (DMSO-d₆,400 MHz) major characteristic peaks: δ (ppm) 0.52-0.61 (m, 2H),0.73-0.76 (m, 2H), 1.89 (br s, 2H), 2.02 (br s, 2H), 3.08-3.21 (m, 2H),3.50 (s, 4H), 3.67-3.72 (m, 1H), 4.53 (s, 1H), 4.82 (s, 1H), 6.04 (s,1H), 7.02 (s, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.32(s, 1H), 7.86 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.16 (s, 1H), 8.93 (d,J=9.2 Hz, 1H), 9.66 (s, 1H). For Compound 69A, LC-MS (m/z): 573 [M+1]⁺;¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 0.46-0.54(m, 2H), 0.70-0.74 (m, 2H), 1.89 (br s, 2H), 2.04 (br s, 2H), 3.15 (s,2H), 3.38-3.48 (m, 4H), 3.60-3.65 (m, 1H), 4.13-4.37 (s, 1H), 4.52 (s,1H), 6.09 (s, 1H), 6.73 (s, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.8Hz, 1H), 7.82-7.90 (m, 2H), 8.09 (s, 1H), 9.27 (d, J=9.2 Hz, 1H), 9.62(s, 1H).

Example 70

To a stirred solution of Compound 1E (500 mg, 2.27 mmol) in THF (8 mL)was added LiOH.H₂O (99 mg, 2.27 mmol) and water (2 mL). The mixture wasstirred at room temperature for 3 h. After reaction, the mixture wasadjusted pH to 1 with 1 M HCl and concentrated by evaporation. Theaqueous phase was extracted with ethyl acetate (50 mL×3). The combinedorganic phase was washed with water and brine, dried over anhydrousNa₂SO₄, and concentrated to render Compound 70A (403 mg, yield 92%) as ayellow solid. LCMS: (m/z) 193 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.97 (m, 3H), 3.07-3.09 (m, 2H), 4.39 (d,J=4.4 Hz, 1H), 7.15-7.19 (m, 4H).

To a solution of(1R,2R)-1-((tert-butyldimethylsilyl)oxy)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-2-amine(392 mg, 1.0 mmol) in DCM (20 mL) was added EDCI (288 mg, 1.5 mmol),HOBt (202 mg, 1.5 mmol) and Compound 70A (192 mg, 1.0 mmol). The mixturewas stirred at room temperature overnight and diluted with DCM (20 mL).It was washed with water (50 mL×2), brine (50 mL×1), dried overanhydrous Na₂SO₄, concentrated, and purified by silica gel columnchromatography (methanol in dichloromathane, 5% v/v) to give Compound70B (360 mg, yield 64%) as a yellow oil. LC-MS (m/z): 567 [M+1]⁺.

To a stirred solution of Compound 70B (360 mg, 0.64 mmol) in DCM (20 mL)was added DMP (324 mg, 0.76 mmol). The mixture was stirred at roomtemperature overnight. It was quenched with sat. aq Na₂SO₃ solution andthen concentrate by evaporation. The aqueous phase was extracted withDCM (50 mL×3). The combined organic phase was washed with water, brine,and dried over anhydrous Na₂SO₄. Filtration and evaporation to drynessgave Compound 70C (210 mg, yield 60%) as a yellow oil. LCMS: (m/z) 565[M+1]⁺.

To a solution of Compound 70C (210 mg, 0.37 mmol) in THF (20 mL) wasadded TBAF (195 mg, 0.74 mmol). The mixture was stirred at roomtemperature overnight, quenched with sat. aq NH₄Cl solution, andconcentrated by evaporation. The aqueous phase was extracted with DCM(50 mL×3). The combined organic phase was washed with water, brine, anddried over anhydrous Na₂SO₄. Removal of solvent led to a crude product,which was purified by prep-HPLC to give Compound 70 (12 mg, yield 7%) asa yellow solid. LC-MS (m/z): 451 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) majorcharacteristic peaks: δ (ppm) 2.07 (s, 4H), 2.87 (m, 3H), 3.21 (m, 4H),3.82 (m, 3H), 4.08 (m, 1H), 4.21 (s, 4H), 4.45 (m, 2H), 4.96 (m, 1H),6.76-6.82 (m, 3H), 7.14 (m, 4H), 7.86 (s, 1H), 11.11 (s, 1H).

Example 71

To a solution of Compound 11C (300 mg, 1.19 mmol) in EtOH (5 mL) wasadded LiOH (43 mg, 1.78 mmol) in water (5 mL). The mixture was stirredat room temperature overnight. After removal of EtOH by evaporation, themixture was adjusted to pH 7 with diluted HCl. lyophilization of thesolution gave Compound 71A (200 mg, crude), which was used for the nextstep without further purification. LC-MS (m/z): 223 [M−1]⁻.

A mixture of Compound 71A (100 mg, 0.45 mmol), EDCI (130 mg, 0.68 mmol),HOBt (91 mg, 0.68 mmol), Intermediate A (125 mg, 0.45 mmol) in DCM (10mL) was stirred at room temperature overnight. After addition of sat. aqNaHCO₃, the mixture was extracted with DCM (50 mL×2), washed with brine(50 mL), dried over Na₂SO₄, and concentrated. The crude product waspurified by prep-HPLC to give Compound 71 (68 mg, yield 31%) as a whitesolid. LC-MS (m/z): 485 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.84 (m, 4H), 3.13 (m, 2H), 3.51 (m, 4H),4.18 (s, 4H), 4.42 (s, 1H), 4.70 (s, 1H), 5.92 (s, 1H), 6.80 (m, 3H),7.65 (m, 1H), 7.81 (m, 1H), 8.05 (s, 1H), 8.19 (m, 1H), 8.59 (s, 1H),9.18 (s, 1H).

Example 72

A mixture of Compound 71 (20 mg, 0.042 mmol) and saturated hydroxylaminesolution in methanol (5 mL) was stirred at 70° C. for 5 h. Afteraddition of sat. aq NH₄Cl (10 mL), the mixture was extracted with DCM(10 mL×2), washed with brine (30 mL), dried over Na₂SO₄, andconcentrated. The crude product was purified by prep-HPLC to giveCompound 72 (3 mg, yield 14%) as a white solid. LC-MS (m/z): 500 [M+1]⁺;¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm) 1.92 (m,4H), 3.11 (m, 2H), 3.55 (m, 4H), 4.21 (s, 4H), 4.58 (s, 1H), 4.80 (s,1H), 5.95 (s, 1H), 6.46 (s, 1H), 6.87 (m, 3H), 7.40 (m, 1H), 7.64 (m,2H), 8.84 (m, 1H), 10.07 (s, 1H), 12.42 (s, 1H).

Example 73

To a stirred solution of Compound 50F (250 mg, 0.84 mmol) in THF (10 mL)was added LiOH.H₂O (71 mg, 1.68 mmol) and water (2 mL). The mixture wasstirred at room temperature for 3 h. After adjusted pH to 1 with 1 MHCl, the mixture was concentrated by evaporation. The aqueous phase wasextracted with ethyl acetate (50 mL×3). The combined organic phase waswashed with water, brine, and dried over anhydrous Na₂SO₄, andconcentrated to give Compound 73A (160 mg, yield 71%) as a yellow solid.LCMS: (m/z) 270 [M+1]⁺.

To a solution of(1R,2R)-1-((tert-butyldimethylsilyl)oxy)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-2-amine(233 mg, 0.59 mmol) in DCM (10 mL) was added EDCI (171 mg, 0.89 mmol),HOBt (120 mg, 0.89 mmol) and Compound 73A (160 mg, 0.59 mmol). Themixture was stirred at 25° C. overnight. After diluted with DCM (20 mL),it was washed with water (50 mL×2), brine (50 mL×1), dried overanhydrous Na₂SO₄, concentrated, and purified by column chromatography onsilica gel (methanol in dichloromethane, 5% v/v) to give Compound 73B(120 mg, yield 31%) as a yellow oil. LC-MS (m/z): 644 [M+1]⁺.

To a stirred solution of Compound 73B (120 mg, 0.19 mmol) in DCM (10 mL)was added DMP (97 mg, 0.23 mmol) and NaHCO₃ (31 mg, 0.37 mmol). Themixture was stirred at 25° C. overnight. After addition with sat. aqNa₂SO₃ solution, the mixture was concentrated by evaporation. Theaqueous phase was extracted with DCM (50 mL×3). The combined organicphase was washed with water, brine, and dried over anhydrous Na₂SO₄.Filtration and evaporation of the solution to dryness gave Compound 73C(110 mg, yield 92%) as a colorless oil. LCMS (m/z): 642 [M+1]⁺.

To a solution of Compound 73C (110 mg, 0.17 mmol) in THF (10 mL) wasadded TBAF (22 mg, 0.09 mmol). The mixture was stirred at 25° C.overnight and followed by quenched with sat. aq NH₄Cl solution. Theaqueous phase was extracted with DCM (50 mL×3). The combined organicphase was washed with water, brine, and dried over anhydrous Na₂SO₄.After removal of the solvents, the crude product was purified byprep-HPLC twice to give Compound 73 (5.9 mg, yield 7%) as a white solid.LC-MS (m/z): 528 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 1.72 (m, 2H), 1.85 (m, 3H), 1.94-1.97 (m, 1H), 2.31 (s,1H), 2.53 (s, 1H), 2.77 (m, 3H), 2.92-3.12 (m, 3H), 3.26-3.28 (m, 3H),4.23-4.24 (m, 5H), 4.62 (d, J=4.8 HZ, 0.36 H), 5.03 (m, 0.64H),6.62-6.72 (m, 1H), 6.79-6.85 (m, 2H), 7.21 (m, 1H), 7.29-7.34 (m, 1H),7.70-7.72 (m, 3H), 7.83-7.86 (m, 1H), 8.66 (m, 1H).

Example 74

A mixture of Compound 63A (1.10 g, 4.58 mmol) and LiOH.H₂O (577 mg,13.75 mmol) in THF/MeOH/H₂O (20/20/10 mL) was stirred at 25° C. for 3 h.It was diluted with ice-water (150 mL) and adjusted to pH 1 with conc.HCl. Filtration to collect the solid gave Compound 74A (900 mg, yield87%) as a white solid. ¹H-NMR (DMSO-d₆, 400 MHz) major characteristicpeaks: δ (ppm) 2.75-2.91 (m, 5H), 3.96 (s, 1H), 7.12-7.24 (m, 3H).

A mixture of Compound 74A (100 mg, 0.44 mmol), EDCI (127 mg, 0.66 mmol),HOBt (89 mg, 0.66 mmol) and(1R,2R)-1-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-2-amine(173 mg, 0.44 mmol) in DCM (10 mL) was stirred at 25° C. overnight. Itwas diluted with ethyl acetate (150 mL), washed with water and brine,and purified by silica gel column chromatography (methanol indichloromethane, from 0% to 8% v/v) to give Compound 74B (230 mg, yield87%) as a white solid. LC-MS (m/z): 601 [M+1]⁺.

A mixture of Compound 74B (200 mg, 0.33 mmol) and DMP (212 mg, 0.50mmol) in DCM (10 mL) was stirred at 25° C. overnight. The mixture wasdiluted with ethyl acetate (150 mL), washed with water and brine, andpurified by silica gel column chromatography (methanol indichloromethane, from 0% to 8% v/v) to afford Compound 74C (160 mg,yield 80%) as a colorless oil. LC-MS (m/z): 599 [M+1]⁺.

A mixture of Compound 74C (160 mg, 0.27 mmol) and Bu₄NF (50 mg) in THF(20 mL) was stirred at 25° C. overnight. The mixture was diluted withethyl acetate (150 mL), washed with water and brine, and purified byprep-HPLC to yield Compound 74 (60 mg, yield 46%) as a white solid.LC-MS (m/z): 485 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristicpeaks: δ (ppm) 1.72 (br s, 4H), 1.87-1.96 (m, 2H), 2.30 (br s, 1H),2.54-2.65 (m, 2H), 2.95-3.03 (m, 3H), 3.12-3.25 (m, 3H), 3.49-3.56 (m,1H), 4.59 (s, 5H), 4.60 (d, J=8.0 Hz, 1H), 5.09 (s, 1H), 6.57-6.63 (m,1H), 6.77-6.85 (m, 2H), 7.10-7.17 (m, 4H).

Example 75

A mixture of 75A (1.00 g, 9.09 mmol) and Pd/C (1.00 g, 10%) in MeOH (20mL) was stirred at 25° C. overnight in the presence of H₂. Then mixturewas filtered to remove Pd/C. The filtrate was evaporated to renderCompound 75B (1.00 g, yield 100%) as a white solid. LC-MS (m/z): 89[M−1]⁻.

A mixture of Compound 75B (57 mg, 0.51 mmol),(1R,2R)-1-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-2-amine(200 mg, 0.51 mmol), EDCI (147 mg, 0.76 mmol) and HOBt (103 mg, 0.76mmol) in DMSO (5 mL) was stirred at 20° C. overnight. It was dilutedwith ethyl acetate (200 mL), washed with water and brine, and purifiedby silica gel column chromatography (methanol in dichloromethane, from0% to 8% v/v) to yield Compound 75C (180 mg, yield 76%) as colorlessoil. LC-MS (m/z): 465 [M+1]⁺.

To a solution of Compound 75C (470 mg, 1.01 mmol) in DCM (10 mL) wasadded DMP (478 mg, 1.11 mmol) at 20° C. The mixture was stirred at 20°C. overnight. The mixture was quenched with Na₂S₂O₃ aqueous solution,diluted with ethyl acetate (200 mL), washed with water and brine, driedwith anhydrous Na₂SO₄, and purified by silica gel column chromatography(methanol in dichloromethane, from 0% to 8% v/v) to afford Compound 75D(320 mg, yield 68%) as colorless oil. LC-MS (m/z): 463 [M+1]⁺.

A mixture of Compound 75D (150 mg, 0.32 mmol), sodium acetate (53 mg,0.64 mmol) and O-phenylhydroxylamine hydrochloride (91 mg, 0.64 mmol) inEtOH (10 mL) was stirred at 85° C. for 3 h. Purification by prep-HPLCgave Compound 75E (100 mg, yield 56%) as a colorless oil. LC-MS (m/z):554 [M+1]⁺.

A mixture of Compound 75E (100 mg, 0.23 mmol) and Bu₄NF (10 mg) in THF(10 mL) was stirred at 20° C. overnight. The mixture was diluted withethyl acetate (150 mL), washed with water and brine, and purified byprep-HPLC to give Compound 75 (22 mg, yield 22%) as a white solid. LC-MS(m/z): 440 [M+1]⁺; ¹H-NMR (MeOD, 400 MHz) major characteristic peaks: δ(ppm) 1.99-2.06 (m, 2H), 2.17 (s, 5H), 3.14-3.23 (m, 2H), 3.43-3.49 (m,1H), 3.59-3.68 (m, 2H), 3.80-3.87 (m, 1H), 4.21 (s, 4H), 4.50-4.55 (m,1H), 4.83 (s, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.87-6.90 (m, 1H), 6.96 (s,1H), 7.12-7.16 (m, 1H), 7.30-7.33 (m, 2H), 7.38-7.42 (m, 2H).

Example 76

A mixture of Compound 71 (30 mg, 0.062 mmol), O-methylhydroxylamine (29mg, 0.62 mmol) in methanol (5 mL) was stirred at 60° C. for 5 h. Afteraddition of sat. aq NH₄Cl (10 mL), the mixture was extracted with DCM(10 mL×2), washed with brine (30 mL×1), dried over Na₂SO₄, andconcentrated. The crude product was purified by prep-HPLC to giveCompound 76 (10 mg, yield: 31%) as a white solid. LC-MS (m/z): 514[M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) major characteristic peaks: δ (ppm)1.88 (m, 4H), 3.10 (m, 2H), 3.61 (m, 4H), 3.96 (m, 3H), 4.20 (m, 4H),4.48 (m, 1H), 4.83 (m, 1H), 5.98 (s, 1H), 6.44 (s, 1H), 6.91 (m, 3H),7.61 (m, 1H), 8.40 (m, 1H), 9.61 (m, 1H).

Example 77

A mixture of NaH (60%, 20 g, 500 mmol), THF (3 L), EtOH (2.5 mL) wascooled to 0° C., ethyl formate (55.5 g, 750 mmol) and Compound 77A (49g, 500 mmol) were added. The mixture was stirred for 6 hrs, and stoodfor 24 hrs. After the addition of EtOH (10 mL), the mixture was stirredfor 1 hr, added water (1 L) and EA (1 L), washed with water (500 mL×2).The aqueous layer was acidified with 6 N HCl, extracted with EA (300mL×2), washed with brine (300 mL×1), dried over anhydrous Na₂SO₄, andpurified by column chromatography on silica (ethyl acetate in Petroleumether, 10% v/v) to give Compound 77B.

To a solution of Compound 77B (23 g, 183 mmol) in MeOH (300 mL) wasadded 2-aminoacetate hydrochloride (23 g, 183 mmol) and NEt₃ (18.4 g,183 mmol). The mixture was stirred at 25° C. for 16 hrs. The mixture wasconcentrated and added water (100 mL), extracted with DCM (100 mL×3),washed with brine (100 mL×1), dried over anhydrous Na₂SO₄, concentratedto give Compound 77C.

To a solution of NaOMe (6.86 g, 127 mmol) in MeOH (200 mL) was addedCompound 77C (25 g, 127 mmol). The mixture was stirred at 90° C. for 3hrs. The mixture was poured into water (500 mL), extracted with EA (100mL×3), washed with water (50 mL×1), dried over anhydrous Na₂SO₄,purified by column chromatography (dichloromethane, 100% v/v) to giveCompound 77D.

A mixture of Compound 77D (1 g, 5.6 mmol) and KOH (0.6 g, 11.2 mmol) inethane-1,2-diol (20 mL) was stirred at 200° C. for 3 hrs. The mixturewas cooled down, added DCM (50 mL), washed with water (50 mL×3), brine(50 mL×1), dried over anhydrous Na₂SO₄, purified by FCC (ethyl acetatein petroleum ether, 0-20% v/v) to give Compound 77E.

To a solution of Compound 77E (200 mg, 1.7 mmol) and NEt₃ (550 mg, 5.1mmol) in DCM (20 mL) was added ethyl 2-chloro-2-oxoacetate (455 mg, 3.4mmol) and stirred at 25° C. for 3 hrs. The mixture was added DCM (50mL), washed with water (50 mL×3), brine (50 mL×1), dried over anhydrousNa₂SO₄, purified by FCC (ethyl acetate in petroleum ether, 0-20% v/v) togive Compound 77F.

To a solution of Compound 77F (350 mg, 1.58 mmol) in EtOH (30 mL) andH₂O (3 mL) was added LiOH.H₂O (133 mg, 3.17 mmol) and stirred at 25° C.for 10 min, concentrated and added water (30 mL), extracted with DCM (20mL×2). The aqueous layer was acidified via the addition of 1 N HCl,extracted with DCM (20 mL×3), dried over anhydrous Na₂SO₄, concentratedto give Compound 77G.

To a solution of Compound 77G (100 mg, 0.5 mmol), EDCI (144 mg, 0.75mmol), HOBt (100 mg, 0.75 mmol) in DCM (10 mL) was added Intermediate A(140 mg, 0.5 mmol). The mixture was stirred at 25° C. for 24 hrs, addedwater (50 mL), extracted with DCM (30 mL×3), dried over anhydrousNa₂SO₄, purified by prep-HPLC to give Compound 77. LCMS: 454 [M+H]⁺; ¹HNMR (CDCl₃, 400 MHz) δ (ppm) 1.73 (m, 4H), 2.10 (m, 5H), 2.51 (m, 2H),2.84 (m, 2H), 2.97 (br, 1H), 3.40 (m, 2H), 3.92 (m, 2H), 4.21 (s, 4H),4.44 (s, 1H), 5.10 (s, 1H), 6.80 (m, 3H), 6.88 (s, 1H), 8.20 (br, 1H),11.02 (br, 1H), 11.49 (br, 1H).

Example 78

A mixture of Compound 73A (200 mg, 0.75 mmol), EDCI (218 mg, 1.13 mmol),HOBt (154 mg, 1.13 mmol), Intermediate F (168 mg, 0.75 mmol) in DCM (20mL) was stirred at room temperature overnight. Then added water,extracted with DCM (50 mL×2), washed with brine (50 mL), dried overNa₂SO₄, concentrated. The crude product was purified by pre-HPLC to giveCompound 78. LC-MS (ESI) m/z: 471 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ(ppm) 2.43 (m, 2H), 3.14 (s, 3H), 3.58 (m, 2H), 4.13 (s, 4H), 4.41 (m,2H), 4.99 (s, 1H), 6.83 (m, 3H), 7.44 (s, 2H), 7.67 (s, 1H), 8.01 (s,1H), 8.19 (s, 1H), 10.96 (s, 1H).

Example 79

A mixture of Compound 73A (254 mg, 1.13 mmol), EDCI.HCl (325 mg, 1.69mmol), HOBt (230 mg, 1.69 mmol) and Intermediate I (350 mg, 1.13 mmol)in DCM (25 mL) was stirred at room temperature overnight. Then themixture was treated with water, extracted with DCM (150 mL×2), washedwith brine (100 mL×1), dried over Na₂SO₄ and concentrated. The crudeproduct was purified with Prep-HPLC to provide Compound 79. LC-MS (ESI)m/z: 517.0 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 0.74-0.76 (d, J=5.2Hz, 4H), 2.15 (s, 4H), 2.98-2.99 (m, 3H), 3.66 (s, 1H), 3.68-3.77 (m,2H), 3.91 (s, 2H), 4.53 (s, 1H), 5.14 (s, 1H), 7.17-7.22 (m, 2H), 7.35(s, 1H), 7.43-7.49 (m, 2H), 7.685-7.688 (d, J=1.2 Hz, 1H), 8.11-8.18 (m,2H), 11.77 (s, 1H).

Example 80

To a solution of Intermediate K (200 mg, 0.72 mmol) and Compound 11E(176 mg, 0.72 mmol) in DCM (10 mL) was added EDCI.HCl (207 mg, 1.08mmol) and HOBt (146 mg, 1.08 mmol) under N₂. The mixture was stirred at30° C. overnight. TLC and LC-MS showed the starting material wasconsumed completely, then water (3 mL) was added to the mixture and thenextracted with DCM (50 mL×3). The combined organic layers were washedwith brine (5 mL×2), dried over anhydrous Na₂SO₄, and concentrated toprovide the crude product. The crude product was purified with Prep-HPLCto provide a racemic mixture (45 mg, Yield: 12%) as a white solid, whichwas further purified by chiral HPLC (AD-H, 0.1% DEA in methanol) tofurnish Compound 80. LC-MS (ESI) m/z: 508 [M+H]⁺, ¹H NMR (MeOD, 400 MHz)δ (ppm) 1.29 (m, 6H), 1.83 (s, 4H), 2.69-2.73 (m, 4H), 2.91 (d, J=6.8Hz, 2H), 4.41 (m, 1H), 4.93 (d, J=3.6 Hz, 1H), 5.08 (m, 1H), 6.56 (d,J=8.4 Hz, 1H), 7.07 (s, 1H), 7.45 (dd, J=2.4, 8.8 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.63 (dd, J=2.4, 8.8 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H),8.09 (d, J=2.8 Hz, 1H).

Example 82

A mixture of Compound 82A (20 g, 89 mmol), methyl acrylate (23 g, 268mmol) Pd(PPh₃)₂Cl₂ (3 g, 45 mmol) and K₂CO₃ (30 g, 223 mmol) in DMF (100mixture was stirred at 100° C. for 12 h, then cooled to roomtemperature, then filtered. The filtrate was treated with water,extracted with DCM (100 mL×2), washed with water (100 mL×3), brine (100mL), dried over Na₂SO₄, and concentrated to furnish the solid, then thesolid was washed with PE, filtered to furnish the crude Compound 82B.

To a solution of Compound 82B (17 g, 74 mmol) in MeOH (200 mL) and THF(80 mL) was added Pd/C (2 g), then the mixture was stirred at roomtemperature for 12 h under H₂, then filtered. The filtrate wasconcentrated to furnish the crude Compound 82C.

To a solution of LiAlH₄ (3 g, 73 mmol) in THF (100 mL) was addeddropwise Compound 82C (17 g, 73 mmol) in THF (50 mL) at −78° C. underN₂, then the mixture was stirred at −78° C. for 30 min, then quenchedwith Na₂SO₄.10H₂O and filtered. The filtrate was concentrated to furnishthe crude Compound 82D.

To a solution of Compound 82D (13 g, 64 mmol) in DCM (100 mL) was addedDMP (32 g, 76 mmol) at 0° C., then the mixture was stirred at roomtemperature for 2 h, then filtered. The filtrate was concentrated andthe residue was purified with column chromatography (ethyl acetate inpetroleum, 10% v/v) to furnish Compound 82E.

Compound 82E (25 g, 0.12 mol) was added to a solution of Na₂S₂O₅ (24 g,0.12 mol) in water (300 mL), then the mixture was stirred for 2 h atroom temperature. And after the addition of NaCN (12 g, 0.24 mol) for 15h, the mixture was diluted with EA (50 mL), extracted with EA (100mL×2), washed with sat. NaHCO₃ (100 mL×2), brine (100 mL), dried overNa₂SO₄, and concentrated to furnish the crude product Compound 82F.

To a solution of Compound 82F (5 g, 22 mmol) in EtOH (50 mL) was bubbleda gentle stream of HCl gas (dried over con. H₂SO₄) at 0° C. for 5 h.Then the mixture was treated with water slowly at 0° C., stirred at roomtemperature for 2 h, then extracted with DCM (100 mL×2), washed withbrine (100 mL), dried over Na₂SO₄, concentrated and purified with columnchromatography (ethyl acetate in petroleum, 10% v/v) to furnish Compound82G.

To a solution of Compound 82G (4 g, 14.5 mmol) in DCM (100 mL) was addedDMP (7.4 g, 17.4 mmol), then the mixture was stirred at room temperaturefor 1 h, then filtered. The filtrate was concentrated and the residuewas purified with column chromatography (10% ethyl acetate in petroleum)to furnish Compound 82H.

To a solution of Compound 82H (2 g, 7.3 mmol) in DCM (50 mL) was addedDAST (5.9 g, 36 mmol), then the mixture was stirred at room temperaturefor 12 h, poured into ice water, extracted with DCM (50 mL×2), washedwith brine (50 mL), dried over Na₂SO₄, concentrated and purified withcolumn chromatography (10% ethyl acetate in petroleum) to furnishCompound 821.

To a solution of Compound 821 (1.8 g, 6.07 mmol) in THF (30 mL) wasadded LiOH (383 mg, 9.1 mmol) in water (2 mL), then the mixture wasstirred at room temperature for 2 h, then evaporated to remove solvent.The mixture was treated with water, adjusted PH to 2 with diluted HCl,then extracted with EA (50 mL×2), washed with brine (50 mL), dried overNa₂SO₄, and concentrated to furnish the Compound 82J.

To a solution of Compound 82J (173 mg, 0.64 mmol) in DCM (50 mL) wasadded EDCI.HCl (186 mg, 0.97 mmol), HOBt (132 mg, 0.97 mmol), and(1R,2R)-2-amino-1-(3-chloro-4-cyclopropoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol(200 mg, 0.97 mmol), then the mixture was stirred at room temperatureovernight. The mixture was treated with water (50 mL), extracted withDCM (50 mL×2), washed with brine (50 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified with Prep-HPLC to provideCompound 82. LC-MS (ESI) m/z: 561 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ(ppm) 0.56 (m, 4H), 2.13 (m, 4H), 2.41 (m, 2H), 2.60 (m, 2H), 2.90 (m,2H), 3.43 (s, 3H), 3.81 (s, 2H), 4.47 (s, 1H), 5.16 (s, 1H), 7.16 (m,3H), 7.40 (m, 2H), 7.49 (s, 1H), 7.56 (s, 1H), 7.68 (s, 1H), 7.75 (m,1H), 7.79 (m, 1H), 11.99 (s, 1H).

Example 83

To a mixture of Compound 11E (106 mg, 0.3 mmol) in dichloromethane (20mL) was added EDCI.HCl (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) andIntermediate H (74 mg, 0.3 mmol). It was stirred at 30° C. for 5 h. Thenit was treated with water (20 mL), extracted with dichloromethane (20mL×3), dried over anhydrous Na₂SO₄, evaporated and purified withPrep-HPLC to furnish trifluoroacetic acid salt of Compound 83. LC-MS(ESI) m/z: 493 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 2.42 (s, 1H),2.60 (s, 1H), 3.55-3.58 (m, 2H), 4.05-4.13 (m, 4H), 4.24 (s, 1H), 4.41(t, J=8 Hz, 1H), 4.80 (s, 1H), 6.64 (s, 1H), 6.72 (d, J=12 Hz, 1H), 6.90(s, 1H), 7.43 (d, J=8 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.70 (s, 1H).

Example 84

A mixture of Intermediate A (100 mg, 0.36 mmol), Compound 82J (96 mg,0.36 mmol), EDCI.HCl (104 mg, 0.54 mmol) and HOBt (73 mg, 0.54 mmol) inDCM (20 mL) was stirred at room temperature overnight. The mixture wastreated with water (50 mL), extracted with DCM (50 mL×2), washed withbrine (50 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified with Prep-HPLC to provide Compound 84. LC-MS (ESI) m/z: 529[M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 2.09 (s, 4H), 2.22 (m, 2H), 2.49(m, 1H), 2.65 (m, 1H), 3.45 (m, 4H), 3.89 (m, 4H), 4.48 (s, 1H), 5.05(s, 1H), 6.80 (s, 2H), 6.90 (s, 1H), 7.24 (m, 2H), 7.41 (m, 1H), 7.52(s, 1H), 7.79 (m, 2H), 7.76 (m, 1H), 11.76 (s, 1H).

Example 85

To a solution of Intermediate L (200 mg, 0.63 mmol) and 11E (185 mg,0.75 mmol) in DCM (10 mL) was added EDCI.HCl (181 mg, 0.94 mmol) andHOBt (127 mg, 0.94 mmol) under N₂. The mixture was stirred at 30° C.overnight. TLC and LC-MS showed the starting material was consumedcompletely, and sat. NaHCO₃ (3 mL) was added to the mixture and thenextracted with DCM (50 mL×3). The combined organic layers were washedwith brine (5 mL×2), dried over anhydrous Na₂SO₄, and concentrated toprovide the crude product. The crude product was purified with Prep-HPLCto provide Compound 85. LC-MS (ESI) m/z: 548 [M+H]⁺, ¹H NMR (MeOD, 400MHz) δ (ppm) 2.08-2.22 (m, 4H), 3.25 (m, 2H), 3.65-3.77 (m, 4H),4.55-4.57 (m, 1H), 4.67-4.72 (m, 2H), 6.71 (d, J=2.8 Hz, 1H), 6.62 (d,J=8.4 Hz, 1H), 7.02 (s, 1H), 7.48 (dd, J=2.0, 8.8 Hz, 1H), 7.59 (d,J=9.2 Hz, 1H), 7.71 (dd, J=2.4, 8.4, 1H), 7.75 (d, J=2.0, Hz, 1H), 8.15(d, J=2.4 Hz, 1H).

Example 86

To a mixture of Compound 82J (99 mg, 0.35 mmol) in dichloromethane (10mL) was added EDCI.HCl (99 mg, 0.52 mmol), HOBt (71 mg, 0.52 mmol) andIntermediate H (94 mg, 0.35 mmol). It was stirred at 30° C. for 2 h.Then it was treated with water (20 mL), extracted with dichloromethane(20 mL×3), dried over anhydrous Na₂SO₄, evaporated and purified withPrep-HPLC to furnish trifluoroacetic acid salt of Compound 86. LC-MS(ESI) m/z: 533 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) of Compound δ (ppm)2.18-2.68 (m, 6H), 3.56-3.59 (m, 2H), 3.72-3.95 (m, 4H), 4.25-4.45 (m,4H), 4.46 (m, 1H), 4.85-4.86 (d, J=2.8 Hz, 1H), 6.75-6.82 (m, 2H),7.28-7.34 (m, 2H), 7.49-7.52 (m, 1H), 7.63 (s, 1H), 7.79-7.90 (m, 2H).

Example 87

To a mixture of Compound 82J (80 mg, 0.3 mmol) in dichloromethane (10mL) was added EDCI.HCl (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) andIntermediate C (118 mg, 0.4 mmol) and the resultant mixture was stirredat 30° C. for 15 h. Then it was treated with water (20 mL), extractedwith dichloromethane (20 mL×3), dried over anhydrous Na₂SO₄, evaporatedand purified with Prep-HPLC to furnish trifluoroacetic acid salt ofCompound 87. LC-MS (ESI) m/z: 557 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) &(ppm) 2.12-2.31 (m, 3H), 2.45-2.52 (m, 1H), 2.62-2.70 (m, 1H), 2.90 (s,1H), 3.01-3.11 (m, 5H), 3.46 (m, 2H), 3.79-3.98 (m, 6H), 4.45 (s, 1H),5.50 (s, 1H), 6.68-6.74 (m, 2H), 7.22-7.24 (m, 1H), 7.39 (d, J=12 Hz,1H), 7.53-7.58 (m, 2H), 7.70 (d, J=12 Hz, 1H), 7.76 (t, J=8 Hz, 1H),11.62 (s, 1H).

Example 88

To a solution of Intermediate L (238 mg, 0.75 mmol) and Compound 82J(200 mg, 0.75 mmol) in DCM (10 mL) was added EDCI.HCl (216 mg, 1.12mmol) and HOBt (152 mg, 1.12 mmol) under N₂. The mixture was stirred at30° C. overnight. TLC and LC-MS showed the starting material wasconsumed completely, then sat. NaHCO₃ (5 mL) was added to the mixtureand then extracted with DCM (50 mL×3). The combined organic layers werewashed with water (5 mL), brine (5 mL), dried over anhydrous sodiumsulphate, and concentrated to offer crude product. The crude product waspurified with Prep-HPLC to offer Compound 88. LC-MS (ESI) m/z: 548[M+H]⁺, ¹H NMR (MeOD, 400 MHz) δ (ppm) 2.06 (m, 2H), 2.17-2.26 (m, 4H),2.49-2.56 (m, 1H), 2.67-2.75 (m, 1H), 3.20-3.26 (m, 2H), 3.57-3.61 (m,1H), 3.67-3.73 (m, 3H), 4.29-4.34 (m, 1H), 4.58-4.67 (m, 2H), 5.02 (d,J=2.8 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 7.27-7.33 (m, 2H), 7.49 (dd,J=2.4, 10.0 Hz, 1H), 7.64 (s, 1H), 7.79-7.88 (m, 3H), 8.25 (d, J=2.4 Hz,1H).

Example 89

To a solution of Compound 73A (114 mg, 0.5 mmol), HATU (285 mg, 0.75mmol) in DCM (5 mL) was added Intermediate H (141 mg, 0.5 mmol). Thenthe reaction was stirred at room temperature for 1.5 h. Then the mixturewas treated with water, extracted with DCM (25 mL×2), washed with brine(50 mL), dried over sodium sulphate and concentrated. The crude productwas purified with purified with Prep-HPLC and chiral HPLC (OJ-H,ethanol-DEA), followed by Prep-HPLC to furnish trifluoroacetic acid saltof Compound 89. LC-MS (ESI) m/z: 489 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ(ppm) 2.41 (m, 2H), 3.31-3.50 (m, 1H), 4.13-4.23 (m, 10H), 4.79-4.80 (d,J=2.8 Hz, 1H), 6.63-6.68 (m, 2H), 7.42-7.48 (m, 2H), 7.65-7.66 (s, 1H),8.10-8.11 (s, 1H).

Example 90

To a solution of Compound 82H (1.1 g, 4.0 mmol) in THF (50 mL) was addedLiOH (252 mg, 6.0 mmol) in water (5 mL) at −10° C., then the mixture wasstirred at −10° C. for 30 min, then added ice water, adjusted pH 2 withdiluted HCl, extracted with EtOAc (50 mL×2). The organic layer wasconcentrated to form a solid, washed with PE, filtered to furnishCompound 90A.

A mixture of Compound 90A (177 mg, 0.72 mmol), Intermediate A (200 mg,0.72 mmol), EDCI.HCl (207 mg, 1.08 mmol), HOBt (147 mg, 1.08 mmol) inDMF (20 mL) was stirred at room temperature overnight, then purifiedwith Prep-HPLC to offer Compound 90. LC-MS (ESI) m/z: 507 [M+H]⁺; ¹H NMR(CDCl₃, 400 MHz) δ (ppm) 2.05 (s, 4H), 2.85 (m, 6H), 3.22 (s, 2H), 3.65(s, 1H), 3.83 (s, 1H), 4.18 (s, 4H), 4.40 (s, 1H), 4.92 (s, 1H), 6.77(s, 2H), 6.84 (s, 1H), 7.30 (m, 1H), 7.38 (m, 2H), 7.59 (s, 1H), 7.73(m, 3H), 11.58 (s, 1H).

Example 91

The solution of Compound 63D (60 mg, 0.24 mmol), Intermediate L (77 mg,0.24 mmol), EDCI.HCl (68 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol) inDCM (5 mL) was stirred at 25° C. for 16 h. Then it was diluted with EA(150 mL), washed with water (50 mL×3) and brine (50×2 mL), dried oversulphate, evaporated and purified with Prep-HPLC to furnish Compound 91.LC-MS (ESI) m/z: 548 [M+H]⁺; ¹H NMR (MeOD, 400 MHz) δ 2.06 (br s, 2H),2.19 (br s, 2H), 2.68-2.76 (m, 3H), 2.84-2.92 (m, 2H), 2.97-3.07 (m,2H), 2.56-3.69 (m, 3H), 3.75 (br s, 1H), 4.65-4.72 (m, 2H), 4.74-4.83(m, 1H), 5.02 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.10-7.15 (m, 3H), 7.83(d, J=8.8 Hz, 1H), 8.24 (s, 1H).

Example 92

To a mixture of Compound 63D (59 mg, 0.24 mmol) and Intermediate H (59mg, 0.2 mmol) in dichloromethane (9 mL) was added EDCI.HCl (58 mg, 0.3mmol), HOBt (41 mg, 0.3 mmol). It was stirred at 30° C. for 2 h. Then itwas treated with water (20 mL), extracted with dichloromethane (20mL×3), dried over anhydrous sodium sulphate, evaporated and purifiedwith Prep-HPLC to furnish trifluoroacetic acid salt of Compound 92.LC-MS (ESI) m/z: 511 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 2.38-3.07(m, 7H), 3.48 (s, 2H), 3.96-4.39 (m, 9H), 5.00 (s, 1H), 6.65-6.73 (m,2H), 7.03-7.12 (m, 3H), 7.50-7.52 (d, J=4 Hz, 1H), 12.33 (br, 1H).

Example 93

To a mixture of Compound 63D (118 mg, 0.48 mmol) in dichloromethane (10mL) was added EDCI.HCl (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol) andIntermediate C (118 mg, 0.4 mmol). It was stirred at 30° C. for 2 h.Then it was treated with water (20 mL), extracted with dichloromethane(20 mL×3), dried over anhydrous sodium sulphate, evaporated and purifiedwith Prep-HPLC to furnish trifluoroacetic acid salt of Compound 93.LC-MS (ESI) m/z: 525 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 2.12 (s,4H), 2.57-2.66 (m, 2H), 2.80-2.93 (m, 5H), 3.47 (s, 2H), 3.77 (s, 2H),4.16-4.24 (m, 4H), 4.44 (s, 1H), 5.06 (s, 1H), 6.68-6.75 (m, 2H),7.03-7.11 (m, 3H), 7.58 (s, 1H), 11.69 (s, 1H).

Example 94

A mixture of Intermediate M (150 mg, 0.48 mmol), EDCI.HCl (138 mg, 0.72mmol), HOBt (97 mg, 0.72 mmol) and Compound 11E (142 mg, 0.58 mmol) inDCM (15 mL) was stirred for 18 h at 25° C. Then the mixture was washedwith saturated NaHCO₃ (15 mL) and brine (15 mL), dried over anhydroussodium sulphate. After evaporation, the crude compound was purified withPrep-HPLC to furnish Compound 94. LC-MS (ESI) m/z: 541 [M+H]⁺; ¹H NMR(CDCl₃, 400 MHz) δ (ppm) 1.26-1.34 (m, 6H), 2.11 (m, 4H), 2.93-3.01 (m,4H), 3.52-3.55 (m, 1H), 3.79 (m, 1H), 4.37-4.43 (m, 1H), 4.52 (m, 1H),5.13 (s, 1H), 6.67 (s, 1H), 6.71 (d, J=4.4 Hz, 1H), 7.10 (d, J=8.4 Hz,1H), 7.32-7.43 (m, 3H), 7.94 (d, J=6.4 Hz, 1H), 11.80 (s, 1H).

Example 95

To a mixture of Compound 73A (180 mg, 0.8 mmol) in dichloromethane (20mL) was added HATU (456 mg, 1.2 mmol), DMF (0.1 mL) and Intermediate C(237 mg, 0.8 mmol). It was stirred at 30° C. for 2 h. Then it wastreated with water (20 mL), extracted with dichloromethane (20 mL×3),dried over anhydrous sodium sulphate, evaporated and purified withPrep-HPLC to furnish the mixture. Then the mixture was further purifiedwith chiral separation, Prep-HPLC to furnish trifluoroacetic acid saltof Compound 95. LC-MS (ESI) m/z: 503 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ(ppm) 2.18 (s, 4H), 2.95-3.08 (m, 2H), 3.52 (s, 2H), 3.93 (s, 2H), 4.23(s, 4H), 4.47 (s, 1H), 5.13 (s, 1H), 6.73 (d, J=12 Hz, 2H), 7.46-7.53(m, 2H), 7.70 (s, 1H), 7.99 (s, 1H), 8.25 (s, 1H), 11.86 (s, 1H).

Example 96

A mixture of Compound 82J (80 mg, 0.3 mmol), EDCI.HCl (86 mg, 0.45mmol), HOBt (61 mg, 0.45 mmol) and Compound 66B (83 mg, 0.3 mmol) in DCM(10 mL) was stirred at room temperature for 5 h. Then the reactionmixture was treated with water (20 mL), extracted with DCM (50 mL×2),washed with brine (50 mL), dried over sodium sulphate and concentratedunder vacuum. The residue was purified with Prep-HPLC to offer Compound96. LC-MS (ESI) m/z: 529 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm)1.21-1.35 (m, 3H), 2.21 (s, 2H), 2.47 (s, 1H), 2.61 (s, 1H), 3.10 (s,2H), 3.39-3.49 (m, 3H), 3.81-3.96 (m, 5H), 4.30-4.38 (m, 2H), 4.98 (s,1H), 6.78-6.86 (m, 3H), 7.25 (d, J=8 Hz, 1H), 7.51 (s, 1H), 7.68-7.77(m, 3H), 12.13 (s, 1H).

Example 97

A mixture of Intermediate K (200 mg, 0.72 mmol), 82J (192 mg, 0.72mmol), EDCI.HCl (206 mg, 1.07 mmol), HOBt (146 mg, 1.07 mmol) in DCM (20mL) was stirred at 25° C. for 4 h, added water, extracted with DCM (50mL×2), washed with brine (50 mL), dried over sodium sulphate,concentrated, and purified with Prep-HPLC to offer Compound 97. LC-MS(ESI) m/z: 529 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 1.20-1.23 (m,6H), 2.07 (s, 4H), 2.23-2.28 (m, 2H), 2.64-2.69 (m, 2H), 3.00 (s, 2H),3.62-3.82 (m, 4H), 4.63 (s, 1H), 4.94 (s, 1H), 5.26 (s, 1H), 6.85 (s,1H), 7.19-7.23 (m, 2H), 7.36-7.39 (m, 1H), 7.52 (s, 1H), 7.65-7.74 (m,2H), 8.04 (s, 2H), 8.41 (s, 1H), 11.54 (s, 1H).

Example 98

To a solution of 89 (12 mg, 0.025 mmol) in MeOH (6 mL) was addedhydroxylamine hydrochloride (34 mg, 0.5 mmol) at 30° C., then thereaction was stirred at 55° C. for 4 h. Then it was purified withPrep-HPLC to furnish Compound 98. LC-MS (ESI) m/z: 504 [M+H]⁺; ¹H NMR(MeOD, 400 MHz) δ (ppm) 2.21-2.61 (m, 2H), 3.37-3.41 (m, 2H), 4.12-4.18(m, 9H), 4.74-4.79 (m, 1H), 6.36 (s, 1H), 6.63-6.71 (m, 2H), 7.26-7.27(m, 1H), 7.28-7.54 (m, 3H).

Example 99

To a solution of Intermediate N (110 mg, 0.397 mmol) in CH₂Cl₂ (5 mL)was added Compound 11E (97 mg, 0.397 mmol), EDCI.HCl (113 mg, 0.595mmol) and HOBt (80 mg, 0.595 mmol). The reaction mixture was stirred for10 hours at 30° C. The solvent was removed under reduced pressure, andthe residue was purified successively by prep. TLC (MeOH in CH₂Cl₂, 10%v/v) and chiral HPLC (co-solvent MeOH (0.1% DEA), column, AD-H 4.6*250mm, 5 um) to offer desired product Compound 99. LC-MS (ESI) m/z: 506[M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 0.73-0.79 (m, 4H), 1.78-1.82 (m,4H), 2.64-2.67 (m, 2H), 2.74-2.76 (m, 2H), 2.97-3.07 (m, 2H), 4.07-4.10(m, 1H), 4.23 (br, 1H), 5.17 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.87 (s,1H), 7.32-7.35 (m, 1H), 7.41-7.44 (m, 1H), 7.53-7.58 (m, 2H), 8.21 (d,J=2.0 Hz, 1H).

Example 100

A mixture of Compound 73A (145 mg, 0.65 mmol), HATU (370 mg, 0.97 mmol),and Compound 66B (180 mg, 0.65 mmol) in DCM (20 mL) and DMF (2 mL) wasstirred at room temperature for 2 h. Then the reaction mixture wastreated with water (20 mL), extracted with DCM (50 mL×2), washed withbrine (50 mL), dried over sodium sulphate and concentrated. The crudeproduct was purified with Prep-HPLC to offer Compound 100. LC-MS (ESI)m/z: 485 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 1.25-1.37 (m, 3H),2.31-2.45 (m, 1H), 3.01-3.15 (m, 1H), 3.47-3.59 (m, 3H), 4.08-4.16 (m,5H), 4.33 (s, 1H), 4.51 (s, 1H), 5.01 (s, 1H), 6.78-6.85 (m, 3H),7.43-7.49 (m, 2H), 7.69 (s, 1H), 7.95 (s, 1H), 8.24 (s, 1H), 11.32 (s,1H).

Example 101

A mixture of Intermediate N (100 mg, 0.36 mmol), Compound 82J (96 mg,0.36 mmol), EDCI.HCl (104 mg, 0.54 mmol), HOBt (74 mg, 0.54 mmol) in DCM(20 mL) was stirred at 25° C. overnight, added water, extracted with DCM(50 mL×2), Brine (50 mL), dried over sodium sulphate, concentrated andpurified with Prep-HPLC to offer Compound 101. LC-MS (ESI) m/z: 528[M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 0.67-0.72 (m, 4H), 2.06 (s, 4H),2.17-2.27 (m, 2H), 2.57-2.71 (m, 2H), 3.04 (s, 2H), 3.53-3.67 (m, 3H),3.88 (s, 2H), 4.67 (s, 1H), 5.23 (s, 1H), 6.01 (s, 1H), 7.10 (s, 1H),7.19-7.24 (m, 2H), 7.37-7.39 (m, 1H), 7.51 (s, 1H), 7.66-7.68 (m, 1H),7.70-7.74 (m, 1H), 8.10 (s, 2H), 8.50 (s, 1H), 11.31 (s, 1H).

Example 102

A mixture of 100 (12 mg, 0.025 mmol) and hydroxylamine hydrochloride (17mg, 0.25 mmol) in MeOH (3 mL) was stirred at room temperature for 4 h.Then it was purified with Prep-HPLC directly to offer Compound 102.LC-MS (ESI) m/z: 500 [M+H]⁺; ¹H NMR (MeOD, 400 MHz) δ (ppm) 1.26-1.35(m, 3H), 3.12 (s, 1H), 3.45-3.52 (m, 2H), 3.78-4.14 (m, 4H), 4.38-4.52(m, 5H), 4.86-4.93 (m, 1H), 6.23 (s, 1H), 6.80-6.94 (m, 3H), 7.29 (s,J=8 Hz, 1H), 7.34-7.41 (m, 1H), 7.44-7.62 (m, 2H).

Example 103

60% NaH (1.04 g, 26 mmol) was added in two portions to isopropyl alcohol(30 mL) at room temperature (about 30° C.) under N₂. The mixture wasstirred at 60° C. for 30 min. Compound 103A (2 g, 11.36 mmol) was addedin two portions and the mixture was stirred at reflux 4 h and at 80° C.overnight. The solution was concentrated in vacuo. Water (100 mL) andethyl acetate (200 mL) were added and the layers were separated. Theaqueous layer was extracted with ethyl acetate (50 mL×3). The combinedorganic layers were washed with water (10 mL×2), brine (10 mL×2) anddried over anhydrous sodium sulphate. After filtration the solvent wasremoved in vacuo. The crude product was subjected to flashchromatography (silica, ethyl acetate in petroleum, 0-10% v/v) to offerCompound 103B.

To a solution of Compound 103B (13 g, 60 mmol) in THF (300 mL) was addedn-BuLi (2.4 M, 25 mL) at −60° C. under N₂ and the resultant mixture wasstirred for 0.5 h, then a solution of Compound A4 (8 g, 20 mmol) in THF(50 mL) was added, then the mixture was stirred at −60° C. for 1 h.After reaction monitored by LC-MS and TLC, added saturated NH₄Clsolution (50 mL), extracted with ethyl acetate (100 mL×3), washed withbrine (100 mL×2), and dried over anhydrous sodium sulphate. The crudeproduct was purified with column chromatography (ethyl acetate inpetroleum, 0-20% v/v) to offer Compound 103C.

Compound 103C (472 mg, 1 mmol) was dissolved in anhydrous THF (10 mL)and cooled down to −70° C. under nitrogen atmosphere. L-Selectride (2mL, 1M solution in THF, 2 mmol) was added dropwise while keeping thetemperature at −70° C. Then the reaction was stirred for 0.5 h at −70°C. After reaction was monitored by TLC, the reaction was quenched withsaturated NH₄Cl solution (30 mL) and extracted with ethyl acetate (30mL×3). The combined organic phases were washed water (30 mL), brine (30mL×2), and dried over anhydrous sodium sulphate. The crude product waspurified with column chromatography (ethyl acetate in petroleum, 0-20%v/v) to offer Compound 103D.

To a solution of Compound 103D (2.1 g, 4.4 mmol) in THF (40 mL) wasadded a solution of TBAF (0.58 g, 2.2 mmol) in THF (10 mL) at 0° C.,then the mixture was stirred at 30° C. overnight. After the reaction wasmonitored by TLC and LC-MS. THF was evaporated. Then the residue wastreated with water (50 mL) and extracted with ethyl acetate (50 mL×3),washed with brine (50 mL), and dried over anhydrous sodium sulphate. Thecrude product was purified with flash column (silica, methanol indichloromethane, 0-10% v/v) to offer Compound 103E.

To a solution of Compound 103E (1.2 g, 3.3 mmol) in dry DCM (20 mL) wasadded Et₃N (1 mL) under N₂, then the mixture was cooled to −40° C., MsCl(0.31 mL, 4 mmol) was added slowly. Then the mixture was stirred at −40°C. about an hour. After reaction was monitored by TLC, the mixture wastreated with water (10 mL) and extracted with DCM (50 mL×3), washed withbrine (50 mL), dried over anhydrous sodium sulphate. The crude productwas purified with flash column (silica, methanol in dichloromethane,0-30% v/v) to offer Compound 103F.

To a solution of Compound 103F (1 g, 2.3 mmol) in THF (40 mL) was addedpyrrolidine (2 mL) under N₂, then the mixture was stirred at 50° C. for16 h. After reaction monitored by LC-MS, the mixture was treated withwater (50 mL) and extracted with EA (50 mL×3), washed with brine (50mL×2), dried over anhydrous sodium sulphate. The crude product waspurified with column chromatography (methanol in dichloromethane, 0-10%v/v) to offer Compound 103G.

To a solution of Compound 103G (400 mg, 0.97 mmol) in EtOH (20 mL) andwater (5 mL) was added LiOH.H₂O (163 mg, 3.87 mmol). The mixture wasstirred at 90° C. overnight, concentrated and added water (50 mL),extracted with DCM (30 mL×3), dried over anhydrous sodium sulphate, andconcentrated to furnish the product Compound 103H.

To a solution of Compound 103H (140 mg, 0.5 mmol) and Compound 11E (123mg, 0.5 mmol) in DMF (5 mL) was added EDCI.HCl (144 mg, 0.75 mmol) andHOBt (101 mg, 0.75 mmol) under N₂. The mixture was stirred at 30° C.overnight. TLC and LC-MS showed the starting material was consumedcompletely, EA (50 mL) was added to the mixture and then washed withwater (50 mL×3), brine (50 mL×1), dried over anhydrous sodium sulphate,and concentrated to offer crude product. The crude product was purifiedwith Prep-HPLC to offer a mixture (50 mg, 20%) as a white solid, thenthe mixture was separated by Chiral-HPLC (Co-solvent EtOH (0.1% DEA),column OJ-H 250*4.6 mm 5 um) to offer Compound 103.

Example 104

A mixture of 95 (18 mg, 0.036 mmol) and hydroxylamine hydrochloride (25mg, 0.36 mmol) in MeOH (3 mL) was stirred at room temperature for 8 h.Then it was purified with Prep-HPLC directly to offer Compound 104.LC-MS (ESI) m/z: 518 [M+H]⁺; ¹H NMR (MeOD, 400 MHz) G (ppm) 2.06-2.18(m, 4H), 3.24 (s, 2H), 3.48-3.83 (m, 4H), 4.15-4.34 (m, 4H), 4.59-4.77(m, 1H), 4.91 (d, J=4 Hz, 1H), 6.39 (s, 1H), 6.80-6.89 (m, 2H),7.35-7.60 (m, 3H), 7.67-7.71 (m, 1H).

Example 105

The mixture of Intermediate 0 (120 mg, 0.34 mmol), EDCI.HCl (98 mg, 0.51mmol), HOBt (69 mg, 0.51 mmol) and Compound 11E (101 mg, 0.41 mmol) inDCM (15 mL) was stirred for 18 h at 25° C. Then the mixture was washedwith saturated NaHCO₃ (10 mL) and brine (10 mL), dried over anhydroussodium sulphate. After evaporation, the crude compound was purified withPrep-HPLC to furnish Compound 105. LC-MS (ESI) m/z: 583 [M+H]⁺; ¹H NMR(CDCl₃, 400 MHz) δ (ppm) 1.75-1.84 (m, 2H), 1.96-2.14 (m, 6H), 2.77-2.87(m, 2H), 3.17-3.20 (m, 1H), 3.55-3.60 (m, 3H), 3.76 (m, 1H), 3.88-4.02(m, 3H), 4.41-4.48 (m, 2H), 4.95 (d, J=4.8 Hz, 1H), 6.79 (d, J=8.4 Hz,1H), 6.87 (s, 1H), 7.19 (dd, J=8.4, 1.6 Hz, 1H), 7.32 (dd, J=8.8, 2.0Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.58 (d, J=2.0Hz, 1H), 9.23 (d, J=8.0 Hz, 1H), 11.87 (s, 1H).

Example 106

To a solution of Compound 82H (310 mg, 1.13 mmol) in ethanol (10 mL) wasadded hydroxylamine hydrochloride (102 mg, 1.47 mmol) and K₂CO₃ (203 mg,1.47 mmol), then the mixture was stirred at 25° C. for 12 h andfiltered. The filtrate was concentrated to furnish the Compound 106A.LC-MS (ESI) m/z: 290 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 1.25 (t,J=6.8 Hz, 3H), 2.98 (s, 4H), 4.17-4.23 (m, 2H), 7.18-7.26 (m, 1H),7.37-7.41 (m, 2H), 7.63 (s, 1H), 7.70-7.73 (m, 2H).

To a solution of Compound 106A (1500 mg, 0.52 mmol) in THF (15 mL) wasadded LiOH (65 mg, 1.55 mmol) in water (2 mL), then the mixture wasstirred at 25° C. for 12 h, then added water, diluted with EA (20 mL),adjusted to PH=2 with diluted HCl, extracted with EA (50 mL×2), brine(50 mL), dried over sodium sulphate, and concentrated to furnish crudeCompound 106B.

A mixture of Compound 106B (135 mg, 0.52 mmol), Intermediate A, EDCI.HCl(149 mg, 0.77 mmol), HOBt (106 mg, 0.77 mmol) in DMF (8 mL) was stirredat 25° C. overnight, purified with Prep-HPLC to offer Compound 106.LC-MS (ESI) m/z: 522 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) & (ppm) 1.97 (s,4H), 2.83-2.87 (m, 6H), 3.09 (s, 1H), 3.49 (s, 1H), 3.72 (s, 2H), 4.14(s, 4H), 4.48 (s, 1H), 4.84 (s, 1H), 6.74-6.79 (m, 2H), 6.87 (s, 1H),7.16-7.23 (m, 1H), 7.36-7.40 (m, 2H), 7.61 (s, 1H), 7.65-7.67 (m, 1H),7.71-7.75 (m, 1H), 11.17 (s, 1H).

Example 107

To a solution of Intermediate K (167 mg, 0.60 mmol) and Compound 22J(150 mg, 0.60 mmol) in DMF (10 mL) was added EDCI.HCl (173 mg, 0.90mmol) and HOBt (122 mg, 0.90 mmol) under N₂. The mixture was stirred at25° C. overnight. TLC and LC-MS showed the starting material wasconsumed completely, sat. NaHCO₃ (5 mL) was added to the mixture andthen extracted with EA (50 mL×3). The combined organic layers werewashed with water (5 mL), brine (5 mL), dried over anhydrous sodiumsulphate, and concentrated to offer crude product. The crude product waspurified with Prep-HPLC to offer Compound 107. LC-MS (ESI) m/z: 512[M+H]⁺, ¹H NMR (MeOD, 400 MHz) & (ppm) 0.97 (d, J 6.0 Hz, 3H), 1.06 (d,J 6.4 Hz, 3H), 1.98-2.01 (m, 2H), 2.13-2.25 (m, 4H), 2.49-2.57 (m, 1H),2.65-2.73 (m, 1H), 3.13-3.21 (m, 2H), 3.52-3.56 (m, 1H), 3.61-3.67 (m,3H), 4.61 (d, J 10.0 Hz, 1H), 4.82-4.85 (m, 1H), 4.97 (d, J 2.4 Hz, 1H),6.79-6.81 (m, 1H), 7.24 (dd, J 8.4, 1.6 Hz, 1H), 7.38-7.44 (m, 2H), 7.57(s, 1H), 7.75-7.79 (m, 3H), 7.82-7.85 (m, 1H), 8.17 (s, 1H).

Example 108

The solution of Intermediate L (230 mg, 0.72 mmol), Compound 22J (150mg, 0.60 mmol), EDCI.HCl (172 mg, 0.90 mmol) and HOBt (122 mg, 0.90mmol) in DCM (10 mL) was stirred at room temperature overnight. Then itwas diluted with EA (150 mL), washed with water (50 mL×3) and brine(50×2 mL), dried over sulphate, evaporated and purified with Prep-HPLCto offer Compound 108. LC-MS (ESI) m/z: 552 [M+H]⁺; ¹H NMR (CDCl₃, 400MHz) δ (ppm) 2.02-2.16 (m, 4H), 2.09-2.36 (m, 2H), 2.53-2.60 (m, 2H),2.77-2.99 (m, 2H), 3.34-3.40 (m, 2H), 3.67-3.77 (m, 2H), 4.42-4.47 (m,2H), 4.54-4.60 (m, 1H), 5.18 (s, 1H), 6.80-6.82 (m, 1H), 7.19-7.21 (m,1H), 7.43-7.46 (m, 2H), 7.53 (s, 1H), 7.61-7.63 (m, 2H), 7.75-7.80 (m,3H), 8.14 (s, 1H), 11.88 (s, 1H).

Example 109

A mixture of Compound 22J (100 mg, 0.40 mmol), EDCI.HCl (115 mg, 0.60mmol) and HOBt (81 mg, 0.60 mmol) in Dichloromethane (20 mL) was stirredat 30° C. for 15 min. Intermediate C (148 mg, 0.50 mmol) was added. Thereaction was stirred at 30° C. for 15 h. It was treated with water (20mL), extracted with dichloromethane (20 mL×3). The organic layer waswashed with water (50 mL×2) and brine (50 mL), dried over anhydroussodium sulphate, evaporated and purified with Prep-HPLC to furnishCompound 109. LC-MS (ESI) m/z: 529 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ(ppm) 2.10 (m, 4H), 2.27 (s, 1H), 2.45-2.54 (m, 1H), 2.63-2.71 (m, 1H),2.84 (s, 1H), 2.98 (s, 1H), 3.42 (s, 2H), 3.77-3.95 (m, 6H), 4.43 (s,1H), 5.04 (s, 1H), 6.68-6.73 (m, 2H), 7.22-7.24 (m, 1H), 7.41-7.47 (m,2H), 7.54 (s, 2H), 7.75-7.80 (m, 3H), 11.59 (s, 1H).

Example 110

The mixture of Intermediate 0 (120 mg, 0.34 mmol), EDCI.HCl (98 mg, 0.51mmol), HOBt (69 mg, 0.51 mmol) and Compound 22J (103 mg, 0.41 mmol) inDCM (15 mL) was stirred for 3 h at 25° C. Then the mixture was washedwith saturated NaHCO₃ (10 mL) and brine (10 mL), dried over anhydroussodium sulphate. After evaporation, the crude compound was purified withPrep-HPLC to furnish Compound 110. LC-MS (ESI) m/z: 587 [M+H]⁺; ¹H NMR(CDCl₃, 400 MHz) δ (ppm) 1.57 (m, 2H), 1.71 (m, 2H), 2.10 (m, 4H),2.23-2.33 (m, 2H), 2.44-2.68 (m, 2H), 2.81-2.95 (m, 2H), 3.32-3.42 (m,4H), 3.77-3.79 (m, 4H), 4.21 (m, 1H), 4.45 (m, 1H), 5.12 (s, 1H), 6.82(d, J=8.0 Hz, 1H), 7.14-7.22 (m, 2H), 7.41-7.48 (m, 3H), 7.59 (s, 1H),7.63 (s, 1H), 7.74-7.80 (m, 3H), 11.7 (s, 1H).

Example 111

A mixture of Compound 90A (160 mg, 0.65 mmol), HATU (370 mg, 0.97 mmol)and DMF (0.5 mL) in Dichloromethane (20 mL) was stirred at 30° C. for 15min. Intermediate C (192 mg, 0.65 mmol) was added. The reaction wasstirred at 30° C. for 4 h. Then water (20 mL) was added to reactionmixture. The resulting mixture was extracted with dichloromethane (20mL×3), dried over anhydrous sodium sulphate, evaporated and purifiedwith Prep-HPLC to furnish trifluoroacetic acid salt of Compound 111.LC-MS (ESI) m/z: 525 [M+H]⁺; ¹H NMR (CDCl₃ & MeOD, 400 MHz) δ (ppm)1.97-2.05 (m, 4H), 2.93-2.97 (m, 3H), 3.12-3.16 (m, 3H), 3.09-3.33 (m,1H), 3.47 (t, J=12 Hz, 1H), 3.62 (s, 1H), 3.76 (s, 1H), 4.14-4.18 (m,4H), 4.23-4.27 (m, 1H), 4.74 (s, 1H), 6.60-6.65 (m, 2H), 7.16 (t, J=8Hz, 1H), 7.27 (d, J=8 Hz, 1H), 7.34 (d, J=12 Hz, 1H), 7.56 (s, 1H),7.61-7.71 (m, 2H).

Example 112

A mixture of Compound 106B (150 mg, 0.57 mmol), Intermediate G (178 mg,0.57 mmol), EDCI.HCl (165 mg, 0.86 mmol), HOBt (117 mg, 0.86 mmol) inDMF (5 mL) was stirred at 25° C. for 12 h, purified with Prep-HPLC tooffer Compound 112. LC-MS (ESI) m/z: 529 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz)δ (ppm) 0.72 (s, 4H), 1.97 (s, 4H), 2.77-2.82 (m, 7H), 3.66 (s, 4H),4.52 (s, 1H), 4.92 (s, 1H), 7.16-7.21 (m, 3H), 7.34-7.38 (m, 3H), 7.57(s, 1H), 7.63-7.65 (m, 1H), 7.68-7.72 (m, 2H), 8.15 (s, 1H), 10.90 (s,1H).

Example 113

To a solution of Compound 22J (100 mg, 0.40 mmol) in Dichloromethane (20mL) was added EDCI.HCl (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol), andthe resultant mixture was stirred at 30° C. for 15 min. thenIntermediate H (140 mg, 0.50 mmol) was added. The reaction was stirredat 30° C. for 15 h. It was poured into ice water (20 mL), extracted withdichloromethane (20 mL×3). The organic layer was washed with water (50mL×2) and brine (30 mL), dried over anhydrous sodium sulphate,evaporated and purified with Prep-HPLC to furnish Compound 113. LC-MS(ESI) m/z: 515 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 2.56-2.66 (m,6H), 3.43 (s, 2H), 3.82-3.95 (m, 6H), 4.18-4.45 (m, 3H), 4.98 (s, 1H),6.66-6.72 (m, 2H), 7.21-7.25 (m, 1H), 7.43-7.54 (m, 4H), 7.75-7.81 (m,3H), 12.25 (s, 1H).

Example 114

To a solution of Intermediate 103H (140 mg, 0.5 mmol) and Compound 82J(134 mg, 0.5 mmol) in DCM (5 mL) was added EDCI.HCl (144 mg, 0.75 mmol)and HOBt (101 mg, 0.75 mmol) under N₂. The mixture was stirred at 30° C.overnight. TLC and LC-MS showed the starting material was consumedcompletely, EA (50 mL) was added to the mixture and then washed withwater (50 mL×3), brine (50 mL×1), dried over anhydrous sodium sulphate,and concentrated to offer crude product. The crude product was purifiedwith Prep-HPLC to offer a mixture (50 mg, Yield: 57%) as a white solid,then the mixture was separated by Chiral-HPLC (Co-solvent EtOH (0.1%DEA), column OZ-H 250*4.6 mm 5 um) to offer Compound 114. LC-MS (ESI)m/z: 530 [M+H]⁺, ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 1.12 (d, J=6.0 Hz, 3H),1.20 (d, J=6.4 Hz, 3H), 2.00 (m, 4H), 2.26 (m, 2H), 2.50 (m, 1H), 2.67(m, 1H), 3.14 (m, 4H), 3.30 (m, 1H), 3.47 (m, 1H), 4.47 (m, 1H), 5.11(m, 2H), 6.73 (s, 1H), 6.82 (m, 1H), 7.21 (m, 2H), 7.41 (m, 1H), 7.51(m, 2H), 7.68 (d, J=8.4 Hz, 1H), 7.74 (m, 1H), 8.05 (d, J=5.2 Hz, 1H).Co-solvent: EtOH (0.1% DEA), column: OZ-H 250*4.6 mm 5 um, Rt: 3.56 min.

Example 115

A mixture of Intermediate C (200 mg, 0.67 mmol), Compound 106B (176 mg,0.67 mmol), EDCI.HCl (194 mg, 1.01 mmol), HOBt (137 mg, 1.01 mmol) inDMF (5 mL) was stirred at 25° C. for 12 h, purified with Prep-HPLC tooffer Compound 115. LC-MS (ESI) m/z: 540 [M+H]⁺, ¹H NMR (CDCl₃, 400 MHz)δ (ppm) 1.99 (s, 4H), 2.84 (s, 6H), 3.14 (s, 1H), 3.45 (s, 1H), 3.74 (s,2H), 4.19 (s, 4H), 4.45 (s, 1H), 4.87 (s, 1H), 6.66-6.69 (m, 2H),7.18-7.23 (m, 1H), 7.35-7.40 (m, 2H), 7.59-7.71 (m, 3H), 7.73-7.75 (m,1H), 11.19 (s, 1H).

Example 116

The mixture of Compound 63D (150 mg, 0.42 mmol), EDCI.HCl (121 mg, 0.63mmol), HOBt (85 mg, 0.63 mmol) and Intermediate O (152 mg, 0.62 mmol) inDCM (15 mL) was stirred for 16 h at 25° C. Then the mixture was washedwith saturated NaHCO₃ (10 mL) and brine (10 mL), dried over anhydroussodium sulphate. After evaporation, the crude compound was purified withPrep-HPLC to furnish Compound 116. LC-MS (ESI) m/z: 583 [M+H]⁺; ¹H NMR(CDCl₃, 400 MHz) δ (ppm) 1.84 (m, 2H), 1.99 (m, 2H), 2.16 (m, 4H), 2.45(d, J=8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 2.83-3.04 (m, 5H), 3.43-3.58(m, 4H), 3.82 (m, 2H), 4.01 (m, 2H), 4.48-4.54 (m, 2H), 5.18 (s, 1H),6.91-6.93 (m, 1H), 7.04-7.11 (m, 3H), 7.18-7.19 (m, 1H), 7.43 (s, 1H),7.50 (s, 1H), 11.75 (s, 1H).

Example 117

A mixture of Compound 22J (188 mg, 0.618 mmol), Intermediate P (155 mg,0.618 mmol), EDCI.HCl (176 mg, 0.927 mmol) and HOBt (125 mg, 0.927 mmol)in DCM (10 mL) was stirred at 25° C. for 16 h. Then it was diluted withethyl acetate (100 mL), washed with water (50 mL×3) and brine (50 mL×2),dried over anhydrous sodium sulfate, concentrated, and purified withprep-HPLC to furnish Compound 117. LC-MS (ESI) m/z: 537 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm) 1.03 (s, 3H), 1.05 (s, 3H), 1.47-1.52 (m,2H), 1.83-1.82 (m, 2H), 1.98-2.02 (m, 2H), 2.27-2.29 (m, 2H), 2.53-2.60(m, 2H), 2.63-2.76 (m, 2H), 3.06-3.40 (m, 2H), 3.43-3.48 (m, 4H), 4.52(s, 1H), 4.72 (s, 1H), 5.82 (s, 4H), 6.63 (d, J=8.8 Hz, 1H), 7.00-7.12(m, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.45-7.52 (m, 2H), 7.68 (s, 1H),7.84-7.90 (m, 3H), 8.35 (d, J=8.8 Hz, 1H), 9.49 (s, 1H).

Example 118

A mixture of Intermediate H (200 mg, 0.71 mol), EDCI.HCl (204, 1.06mmol), HOBt (145, 1.01 mmol) and Compound 106B (185 mg, 0.71 mol) in DMF(5 mL) was stirred at room temperature overnight. Then the reactionmixture was purified with prep-HPLC to give Compound 118. LC-MS (ESI)m/z: 526 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ (ppm) 2.15 (s, 1H), 2.50 (m,1H), 2.81-2.90 (m, 4H), 3.27-3.37 (m, 2H), 3.76 (s, 3H), 4.15-4.17 (m,5H), 4.29 (s, 1H), 4.82 (s, 1H), 6.61-6.64 (m, 2H), 7.18-7.22 (m, 1H),7.34-7.39 (m, 2H), 7.52 (s, 1H), 7.59 (s, 1H), 7.65-7.67 (m, 1H),7.71-7.74 (m, 1H), 11.37 (s, 1H).

Example 119

A mixture of Intermediate P (150 mg, 0.490 mmol), Compound 11E (121 mg,0.490 mmol), EDCI.HCl (140 mg, 0.740 mmol) and HOBt (100 mg, 0.740 mmol)in DCM/Et₃N (10/0.5 mL) was stirred at 25° C. for 16 h. Then it wasdiluted with ethyl acetate (100 mL), washed with water (50 mL×3) andbrine (50 mL×2), dried over anhydrous sodium sulfate, concentrated, andpurified with prep-HPLC to furnish Compound 119. LC-MS (ESI) m/z: 533[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm) 1.24 (s, 6H), 1.62-1.67 (m,2H), 1.84-1.90 (m, 2H), 2.00 (s, 2H), 2.57-2.60 (m, 2H), 3.06-3.18 (m,2H), 3.41-3.47 (m, 4H), 4.46-4.51 (m, 1H), 4.72 (s, 1H), 5.82 (s, 1H),5.58 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.95-7.00 (m, 2H), 7.53 (d, J=6.8Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.86 (d, J=9.2 Hz, 1H),9.48 (s, 1H).

Example 120

To a solution of Intermediate N (130 mg, 0.52 mmol) in dichloromethane(5 mL) was added Compound 22J (120 mg, 0.433 mmol), EDCI.HCl (149 mg,0.7794 mmol), and HOBt (107 mg, 0.7794 mmol). The mixture was stirred at30° C. for 2 h. The mixture was evaporated in vacuo to furnish the crudecompound. The crude compound was purified with prep-HPLC to furnish awhite solid (83 mg, yield 37%), which was separated by chiral HPLC(co-solvent IPA (0.5% DEA), column AD-H 250*4.6 mm 5 um) to giveCompound 120. LC-MS (ESI) m/z: 510 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ(ppm) 0.46-0.61 (m, 4H), 1.78-1.80 (m, 4H), 2.26-2.30 (m, 2H), 2.56-2.63(m, 5H), 2.73-2.81 (m, 3H), 3.76-3.79 (m, 1H), 4.36 (brs, 1H), 4.96 (d,J=2.8 Hz, 1H), 6.88-6.89 (m, 1H), 7.27-7.29 (m, 1H), 7.41-7.45 (m, 2H),7.59 (s, 1H), 7.75-7.81 (m, 4H), 8.16 (s, 1H). Co-solvent: IPA (0.5%DEA), column: AD-H 250*4.6 mm 5 um, Rt: 3.51 min.

Example 121

A mixture of Intermediate Q (150 mg, 0.41 mmol), EDCI.HCl (118 mg, 0.62mmol), HOBt (84 mg, 0.62 mmol) and Compound 22J (103 mg, 0.41 mmol) inDCM (5 mL) was stirred for 18 h at 25° C. Then the mixture was washedwith water (50 mL) and brine (50 mL) and dried over anhydrous sodiumsulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 121. LC-MS (ESI) m/z: 600 [M+H]⁺; ¹H-NMR(MEOD, 400 MHz) & (ppm) 1.65-2.11 (m, 11H), 2.49-3.20 (m, 10H),3.54-3.66 (m, 4H), 4.31 (s, 1H), 4.58-4.61 (d, J=10 Hz, 1H), 4.91 (s,1H), 6.93-6.95 (m, 1H), 7.19-7.30 (m, 2H), 7.39-7.52 (m, 4H), 7.74-7.76(m, 3H).

Example 122

A mixture of Intermediate I (117 mg, 0.4 mmol), EDCI.HCl (114 mg, 0.59mmol), HOBt (78 mg, 0.59 mmol) and Compound 11E (88.5 mg, 0.4 mmol) inDCM (15 mL) was stirred at room temperature overnight. Then the reactionmixture was treated with water (20 mL), extracted with DCM (50 mL×2),washed with brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated. The crude product was purified with prep-HPLC to giveCompound 122. LC-MS (ESI) m/z: 503 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) &(ppm) 0.67-0.75 (m, 4H), 2.35-2.36 (m, 1H), 2.64 (s, 1H), 3.48 (s, 1H),3.59-3.69 (m, 2H), 4.0 (s, 2H), 4.35-4.63 (m, 5H), 4.99 (s, 1H),7.09-7.11 (m, 1H), 7.30 (s, 1H), 7.35-7.40 (m, 2H), 7.60 (s, 1H),8.04-8.06 (d, J=8.0 Hz, 1H), 8.21 (s, 1H), 11.38 (s, 1H).

Example 123

A mixture of Intermediate Q (150 mg, 0.41 mmol), EDCI.HCl (118 mg, 0.62mmol), HOBt (84 mg, 0.62 mmol) and Compound 11E (101 mg, 0.41 mmol) inDCM (5 mL) was stirred for 18 h at 25° C. Then the mixture was washedwith water (50 mL) and brine (50 mL), and dried over anhydrous sodiumsulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 123. LC-MS (ESI) m/z: 596 [M+H]⁺; ¹H-NMR(MeOD, 400 MHz) δ (ppm) 2.06-2.28 (m, 8H), 2.92 (s, 3H), 3.13-3.32 (m,4H), 3.42-3.76 (m, 6H), 4.60-4.68 (m, 2H), 4.96 (s, 1H), 6.69-6.78 (m,1H), 6.87-6.95 (m, 1H), 7.27-7.29 (m, 1H), 7.28 (s, 2H), 7.57-7.59 (m,1H), 7.74 (m, 1H).

Example 124

A mixture of Intermediate R (180 mg, 0.530 mmol), Compound 22J (132 mg,0.530 mmol), EDCI.HCl (153 mg, 0.800 mmol) and HOBt (108 mg, 0.800 mmol)in DCM (10 mL) was stirred at 25° C. for 16 h. Then it was diluted withethyl acetate (100 mL), washed with water (200 mL) and brine (200 mL),dried over anhydrous sodium sulfate, concentrated, and purified withprep-HPLC to furnish Compound 124. LC-MS (ESI) m/z: 572 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm) 1.86-1.90 (m, 2H), 2.00-2.19 (m, 4H),2.50-2.68 (m, 6H), 3.07-3.20 (m, 2H), 3.34-3.40 (m, 4H), 3.42-3.49 (m,4H), 4.47-4.53 (m, 1H), 4.83 (s, 2H), 6.03 (s, 1H), 6.98 (d J=8.4 Hz,1H), 7.25-7.34 (m, 2H), 7.38 (s, 1H), 7.45-7.53 (m, 2H), 7.66 (s, 1H),7.84-7.90 (m, 3H), 8.42 (d, J=8.4 Hz, 1H).

Example 125

A mixture of Intermediate S (140 mg, 0.48 mmol), EDCI.HCl (137 mg, 0.72mmol), HOBt (97 mg, 0.72 mmol) and Compound 22J (120 mg, 0.48 mmol) inDCM (5 mL) was stirred for 18 h at 25° C. Then the mixture was washedwith H₂O (50 mL) and brine (50 mL), and dried over anhydrous sodiumsulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 125. LC-MS (ESI) m/z: 527 [M+H]⁺; ¹H-NMR(CDCl₃, 400 MHz) δ (ppm) 0.51-0.52 (m, 4H), 2.08 (s, 4H), 2.22-2.47 (m,2H), 2.49-2.53 (m, 1H), 2.62-2.69 (m, 1H), 2.81-2.95 (m, 2H), 3.41-3.42(m, 3H), 3.76 (s, 2H), 4.46-4.47 (m, 1H), 5.12 (s, 1H), 7.05-7.22 (m,4H), 7.41-7.47 (m, 2H), 7.52 (s, 1H), 7.59-7.61 (d, J=8.0 Hz, 1H),7.74-7.79 (m, 3H), 11.7 (s, 1H).

Example 126

A mixture of Intermediate S (140 mg, 0.48 mmol), EDCI.HCl (137 mg, 0.72mmol), HOBt (97 mg, 0.72 mmol) and Compound 11E (119 mg, 0.48 mmol) inDCM (5 mL) was stirred for 18 h at 25° C. Then the mixture was washedwith H₂O (50 mL) and brine (50 mL), and dried over anhydrous sodiumsulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 126. LC-MS (ESI) m/z: 523 [M+H]⁺; ¹H-NMR(CDCl₃, 400 MHz) δ (ppm) 0.66-0.74 (m, 4H), 2.11 (s, 4H), 2.95-3.02 (m,2H), 3.41-3.65 (m, 5H), 4.47 (s, 1H), 5.10 (s, 1H), 6.74 (s, 1H),6.68-7.15 (m, 3H), 7.32-7.35 (m, 1H), 7.39-7.41 (d, J=8.8 Hz, 1H), 7.55(d, J=1.6 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 11.45 (s, 1H).

Example 127

A mixture of Intermediate R (150 mg, 0.442 mmol), Compound 11E (109 mg,0.442 mmol), EDCI.HCl (127 mg, 0.663 mmol) and HOBt (90 mg, 0.663 mmol)in DCM/Et₃N (10/0.3 mL) was stirred at 25° C. for 16 h. Then it wasdiluted with ethyl acetate (100 mL), washed with water (200 mL) andbrine (200 mL), dried over anhydrous sodium sulfate, concentrated, andpurified with prep-HPLC to furnish Compound 127. LC-MS (ESI) m/z: 568[M+H]⁺; ¹H-NMR (MeOD, 400 MHz) & (ppm) 2.06 (s, 2H), 2.20 (s, 2H),2.75-2.88 (m, 4H), 3.17-3.22 (m, 2H), 3.58-3.70 (m, 4H), 3.75-3.83 (m,4H), 4.65-4.69 (m, 1H), 4.93 (s, 1H), 6.68 (s, 1H), 6.82 (d, J=8.0 Hz,1H), 7.24 (d, J=8.0 Hz, 1H), 7.42-7.48 (m, 2H), 7.59 (d, J=8.0 Hz, 1H),7.79 (s, 1H).

Example 128

To a solution of Intermediate T (100 mg, 0.28 mmol) and Compound 11E (69mg, 0.28 mmol) in DMF (10 mL) was added EDCI.HCl (82 mg, 0.42 mmol) andHOBt (58 mg, 0.42 mmol) under nitrogen. The mixture was stirred at 25°C. overnight. TLC and LC-MS showed the starting material was consumedcompletely, sat. sodium bicarbonate (3 mL) was added to the mixture andthen extracted with EA (50 mL×3). The combined organic layers werewashed with water (5 mL×3) and brine (5 mL), dried over anhydrous sodiumsulfate, and concentrated to offer the crude product. The crude productwas purified with prep-HPLC to offer Compound 128. LC-MS (ESI) m/z: 582[M+H]⁺. ¹H-NMR (CDCl₃, 400 MHz) δ (ppm) 2.16-2.17 (m, 4H), 2.39-2.44 (m,1H), 2.75-2.83 (m, 1H), 2.92-3.01 (m, 2H), 3.45-3.54 (m, 4H), 3.76 (s,2H), 4.14-4.16 (m, 4H), 4.44-4.53 (m, 3H), 5.08 (d, J=2.8 Hz, 1H), 6.62(d, J=8.4 Hz, 1H), 6.81 (s, 1H), 7.12 (dd, J=2.0, 8.8 Hz, 1H), 7.34-7.38(m, 2H), 7.43 (d, J=8.8 Hz, 1H), 7.58 (d, J=2.0, 1H), 8.08 (d, J=8.8 Hz,1H), 11.95 (brs, 1H), 13.25 (brs, 1H).

Example 129

A mixture of Intermediate U (108 mg, 0.33 mmol), EDCI.HCl (96 mg, 0.50mmol), HOBt (67 mg, 0.50 mmol) and Compound 22J (84 mg, 0.33 mmol) inDCM (15 mL) was stirred at room temperature for 4 hours. Then thereaction mixture was treated with water (20 mL), extracted with DCM (50mL×2), washed with brine (50 mL), dried over sodium sulfate, andconcentrated. The crude product was purified with prep-HPLC to furnishCompound 129. LC-MS (ESI) m/z: 559 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ(ppm) 2.04-2.40 (m, 7H), 2.52-2.59 (m, 1H), 2.85-2.97 (m, 2H), 3.34-3.77(m, 4H), 4.46-4.60 (m, 6H), 5.11 (s, 1H), 6.24-6.26 (d, J=8.0 Hz, 1H),7.14-7.20 (m, 2H), 7.42-7.48 (m, 4H), 7.60-7.63 (m, 1H), 7.75-7.81 (m,3H).

Example 130

A mixture of Intermediate U (108 mg, 0.33 mmol), EDCI.HCl (96 mg, 0.50mmol), HOBt (67 mg, 0.50 mmol) and Compound 11E (82 mg, 0.33 mmol) inDCM (15 mL) was stirred at room temperature for 4 hours. Then thereaction mixture was treated with water (20 mL), extracted with DCM (50mL×2), washed with brine (50 mL), dried over sodium sulfate, andconcentrated. The crude product was purified with prep-HPLC to furnishCompound 130. LC-MS (ESI) m/z: 555 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ(ppm) 2.13 (s, 4H), 2.96-3.09 (m, 2H), 3.22-3.88 (m, 4H), 4.52 (s, 1H),4.67-4.74 (m, 2H), 4.91-4.96 (m, 3H), 5.12 (s, 1H), 6.18-6.20 (d, J=8.4Hz, 1H), 6.72 (s, 1H), 7.06-7.08 (m, 1H), 7.33-7.42 (m, 3H), 7.58 (s,1H), 7.96 (m, 1H), 11.65 (s, 1H).

Example 131

To a solution of Intermediate T (100 mg, 0.28 mmol) and Compound 22J (71mg, 0.28 mmol) in DCM (10 mL) was added EDCI.HCl (81 mg, 0.42 mmol) andHOBt (57 mg, 0.42 mmol) under nitrogen. The mixture was stirred at 25°C. overnight. TLC and LC-MS showed the starting material was consumedcompletely, then sat. sodium bicarbonate (5 mL) was added to the mixtureand then extracted with EA (50 mL×3). The combined organic layers werewashed with water (5 mL) and brine (5 mL), dried over anhydrous sodiumsulfate, and concentrated to offer the crude product. The crude productwas purified with prep-HPLC to offer Compound 131. LC-MS (ESI) m/z: 586[M+H]⁺. ¹H-NMR (MeOD, 400 MHz) δ (ppm) 2.03-2.22 (m, 8H), 2.34-2.42 (m,1H), 2.51-2.59 (m, 1H), 2.90-3.01 (m, 2H), 3.15-3.17 (m, 1H), 3.23-3.24(m, 1H), 3.54-3.58 (m, 1H), 3.63-3.68 (m, 3H), 3.74-3.78 (m, 2H),3.82-3.93 (m, 2H), 4.01-4.04 (m, 2H), 4.64 (d, J=10.4 Hz, 1H), 4.96 (d,J=2.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.0, 8.4 Hz, 1H),7.34 (dd, J=2.0, 8.4 Hz, 1H), 7.46-7.52 (m, 3H), 7.57 (s, 1H), 7.81-7.88(m, 3H).

Example 132

To a suspension of aluminum trichloride (1.61 g, 12 mmol) and ethylchloroacetate (1.63 g, 12 mmol) in dichloromethane (60 mL) was addedCompound 132A (1.62 g, 10 mmol) in dichloromethane (15 mL) dropwise atroom temperature overnight. After 24 h a solution of ice water (100 mL)and saturated sodium bicarbonate solution (100 mL) was added dropwise.The aqueous layer was extracted with dichloromethane (50 mL×3). Thecombined organics were washed with brine (200 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 2% v/v) to give the Compound 132B.

To a solution of Compound 132B (2.62 g, 10 mmol) in dichloromethane (350mL) was added DAST (4 mL) at room temperature. The reaction mixture wasstirred at room temperature. After 14 h, the mixture was poured into icewater (50 mL) and extracted with dichloromethane (50 mL×2). The combinedorganics were washed with brine (200 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated. Purification by silica gelchromatography (ethyl acetate in petroleum ether, 2% v/v) gave theCompound 132C.

To a solution of Compound 132C (284 mg, 1 mmol) in ethanol/water (16 mL)was added LiOH H₂O (84 mg, 2 mmol). The mixture was stirred at roomtemperature overnight. After the completion of the reaction, the mixturewas adjusted to pH 2 with aqueous HCl solution (3 N, 40 mL) andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (200 mL), dried over anhydrous sodium sulfate, andconcentrated to furnish Compound 132D.

To a solution of 132D (256 mg, 1 mmol) in DCM (30 mL) was addedIntermediate A (278 mg, 1 mmol), EDCI.HCl (286 mg, 1.5 mmol), HOBt (202mg, 1.5 mmol), and DIPEA (1 mL). The mixture was stirred at roomtemperature overnight. The reaction mixture was diluted by DCM (30 mL),washed with brine (50 mL), dried over sodium sulfate, and concentratedto furnish the crude product, which was purified with prep-HPLC tofurnish Compound 132. LC-MS (ESI) m/z: 517 [M+H]⁺, ¹H-NMR (CDCl₃, 400MHz) δ (ppm) 1.65-1.68 (m, 4H), 2.53-2.63 (m, 4H), 2.86-2.88 (m, 2H),4.02-4.15 (m, 5H), 4.94-4.95 (m, 1H), 6.66-6.69 (m, 3H), 6.89-6.70 (m,1H), 7.33-7.40 (m, 2H), 7.64-7.79 (m, 4H).

Example 133

To a stirred suspension of AlCl₃ (8.5 g, 64 mmol) in dichloromethane (40mL) was added dropwise ethyl 2-chloro-2-oxoacetate (8.7 g, 64 mmol) at−10° C. The mixture was stirred at −10° C. for 15 minutes. Compound 133A(5 g, 32 mmol) was added dropwise at −10° C. The resulting mixture wasstirred at 20° C. for 15 hours. The mixture was poured into ice water(100 mL) to quench the reaction and extracted with dichloromethane (50mL×3). The combined organic layers were washed with saturated sodiumbicarbonate solution (200 mL) and brine (200 mL), dried over anhydroussodium sulfate, and concentrated to give a crude compound. The crudeproduct was purified with flash column chromatography on silica gel(petroleum ether) to furnish Compound 133B.

A mixture of Compound 133B (3.7 g, 14.4 mmol), 4-fluorophenylboronicacid (2.4 g, 17.3 mmol), Pd(PPh₃)₄ (497 mg, 0.4 mmol) and K₃PO₄ intoluene (40 mL) was heated to reflux, stirred for 3 h, and filtered. Thefiltrate was concentrated to give a crude compound. The crude productwas purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 10% v/v) to give Compound 133C.

To a solution of Compound 133C (1.1 g, 4 mmol) in THF/water (30 mL,15:1, v/v) was added LiOH H₂O (250 mg, 6 mmol). The mixture was stirredat −10° C. for 3 h. After the reaction was completed, it was adjusted topH 6 with 3 N HCl and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were concentrated in vacuo to give Compound133D.

A mixture of Compound 133D (195 mg, 0.8 mmol), Intermediate C (237 mg,0.8 mmol), HATU (456 mg, 1.2 mmol) and in dichloromethane (20 mL) wasstirred at 30° C. for 15 h. Then it was treated with water (20 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuum and purified with prep-HPLC to furnishCompound 133. LC-MS (ESI) m/z: 524 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ(ppm) 2.14 (s, 5H), 3.11 (s, 2H), 3.51 (s, 1H), 3.79 (s, 1H), 3.93 (s,2H), 4.16-4.21 (m, 4H), 4.52 (s, 1H), 5.04 (s, 1H), 6.72 (t, J=8 Hz,2H), 7.14 (t, J=8 Hz, 2H), 7.54-7.57 (m, 4H), 7.82 (d, J=8 Hz, 1H), 8.08(d, J=8 Hz, 2H), 9.21 (s, 1H).

Example 134

A mixture of Intermediate I (100 mg, 0.33 mmol), EDCI.HCl (97 mg, 0.51mmol), HOBt (69 mg, 0.51 mmol) and Compound 82J (91 mg, 0.33 mmol) inDMF (5 mL) was stirred at room temperature overnight. Then the reactionmixture was purified with prep-HPLC to offer Compound 134. LC-MS (ESI)m/z: 547 [M+H]⁺; 1H-NMR (CDCl₃, 400 MHz) δ (ppm) 0.47-0.55 (m, 4H), 2.22(s, 2H), 2.40 (s, 2H), 2.56 (s, 2H), 3.40-3.50 (m, 3H), 3.96 (s, 2H),4.34 (s, 3H), 5.05 (s, 1H), 7.15-7.22 (m, 4H), 7.37-7.42 (m, 2H), 7.48(s, 1H), 7.61 (s, 1H), 7.68-7.71 (m, 1H), 7.75-7.79 (s, 1H), 12.13 (s,1H).

Example 135

A mixture of Compound 132D (256 mg, 1 mmol), Intermediate C (296 mg, 1mmol), EDCI.HCl (286 mg, 1.5 mmol) and HOBt (202 mg, 1.5 mmol) in DCM(30 mL) was stirred at 25° C. for 16 h. Then it was diluted with DCM (70mL), washed with water (50 mL×3) and brine (50 mL×2), dried overanhydrous sodium sulfate, concentrated, and purified with prep-HPLC tofurnish Compound 135. LC-MS (ESI) m/z: 535 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz) δ (ppm) 2.10-2.11 (m, 4H), 2.86-3.01 (m, 4H), 3.49-3.51 (m, 2H),4.05-4.10 (m, 4H), 4.37-4.39 (m, 1H), 5.03 (s, 1H), 6.51 (s, 1H), 6.68(d, J=2 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.47-7.50 (m, 1H), 7.75 (d, J=2Hz, 1H), 7.74-7.84 (m, 3H), 7.90 (s, 1H), 11.84 (s, 1H).

Example 136

A mixture of Compound 79 (38 mg, 0.74 mmol), hydroxylamine hydrochloride(138 mg, 2 mmol) and methanol (9 mL) was stirred at 50° C. overnight.Then the mixture was purified with prep-HPLC to offer Compound 136.LC-MS (ESI) m/z: 532.1 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 0.74-0.86(m, 4H), 2.05-2.19 (m, 4H), 3.25-3.30 (m, 1H), 3.52-3.58 (m, 1H),3.72-3.76 (m, 1H), 3.84-3.89 (m, 3H), 4.81-4.85 (m, 1H), 5.02 (d, J=2.4Hz, 1H), 5.97 (s, 1H), 7.32-7.36 (m, 1H), 7.40 (s, 2H), 7.44-7.47 (d,J=8.4 Hz, 2H), 7.54-7.56 (m, 2H).

Example 137

A mixture of Intermediate I (100 mg, 0.33 mmol), EDCI.HCl (97 mg, 0.51mmol), HOBt (69 mg, 0.51 mmol) and Compound 106B (88 mg, 0.33 mmol) inDMF (5 mL) was stirred at room temperature overnight. Then the reactionmixture was purified with prep-HPLC to offer Compound 137. LC-MS (ESI)m/z: 540 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ (ppm) 0.71-0.72 (m, 4H), 1.26(s, 1H), 2.11 (s, 1H), 2.46 (s, 1H), 2.78-2.82 (m, 4H), 3.22 (s, 1H),3.65 (s, 3H), 4.10-4.18 (m, 2H), 4.33 (s, 1H), 4.83 (s, 1H), 7.10-7.22(m, 3H), 7.32-7.38 (m, 3H), 7.58 (s, 1H), 7.62-7.65 (m, 1H), 7.71-7.75(m, 1H), 11.02 (s, 1H).

Example 138

A mixture of Compound 133 (41 mg, 0.078 mmol) and hydroxylaminehydrochloride (109 mg, 1.56 mmol) in MeOH (10 mL) was stirred at roomtemperature for 4 h. Then it was purified with prep-HPLC directly tooffer Compound 138. LC-MS (ESI) m/z: 538 [M+H]⁺; 1H-NMR (MeOD, 400 MHz)δ (ppm) 2.02 (s, 2H), 2.20 (s, 2H), 3.12-3.28 (m, 2H), 3.45-3.87 (m,4H), 4.26-4.60 (m, 5H), 4.78-4.82 (m, 1H), 6.82 (t, J=12 Hz, 2H),7.17-7.42 (m, 4H), 7.53-7.68 (m, 4H).

Example 139

A mixture of Compound 132D (256 mg, 1 mmol), Intermediate G (296 mg, 1mmol), EDCI.HCl (286 mg, 1.5 mmol) and HOBt (202 mg, 1.5 mmol) in DCM(30 mL) was stirred at 25° C. for 16 h. Then it was diluted with DCM (70mL), washed with water (50 mL×3) and brine (50 mL×2), dried overanhydrous sodium sulfate, concentrated, and purified with prep-HPLC tofurnish Compound 139. LC-MS (ESI) m/z: 549 [M+H]⁺; 1H-NMR (CDCl₃, 400MHz) & (ppm) 0.69-0.71 (m, 4H), 1.65-1.68 (m, 4H), 2.34-2.37 (m, 4H),2.64-2.68 (m, 2H), 3.51-3.52 (m, 1H), 4.15 (s, 1H), 5.09 (s, 1H),6.91-6.92 (m, 1H), 7.12-7.13 (m, 2H), 7.35 (s, 1H), 6.94 (m, 1H),7.50-7.52 (t, J=4.8 Hz, 2H), 7.78-7.86 (m, 3H), 7.96 (s, 1H).

Example 140

To a solution of Compound 133C (1.78 g, 6.54 mmol) in drydichloromethane (40 mL) was added DAST (2.2 mL, 16.36 mmol). Then themixture was stirred at 25° C. for 14 h. After the reaction wascompleted, dichloromethane (25 mL) was added. The organic layer waswashed with water (50 mL), followed by aq. sodium bicarbonate (30 mL)and brine (50 mL), dried over sodium sulfate and concentrated to providethe crude product. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v)to provide Compound 140A.

To a solution of Compound 140A (2.3 g, 7.8 mmol) in THF/water/MeOH (30mL, 1:1:1, v/v) was added LiOH.H₂O (493 mg, 11.7 mmol). The mixture wasstirred at 28° C. for 1 h. After the reaction was completed, it wasadjusted to pH to 6 with 2 N HCl and extracted with ethyl acetate (60mL×3). The combined organic layers were concentrated in vacuum toprovide the crude product Compound 140B.

To a solution of Compound 140B (133 mg, 0.5 mmol), Intermediate C (156mg, 0.53 mmol), and EDCI.HCl (144 mg, 0.75 mmol) in dichloromethane (20mL) was added HOBt (102 mg, 0.75 mmol) at 19° C., then the reaction wasstirred at 19° C. for 4 h. Then it was treated with water (20 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuum and purified with prep-HPLC to furnishCompound 140. LC-MS (ESI) m/z: 545 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ(ppm) 2.12 (m, 4H), 2.90-3.10 (m, 2H), 3.45-3.48 (m, 2H), 3.75-3.85 (m,2H), 4.11-4.12 (m, 4H), 4.15-4.22 (m, 1H), 4.90-4.91 (d, J=2.8 Hz, 1H),6.57-6.67 (m, 2H), 7.14-7.19 (m, 2H), 7.43-7.46 (m, 2H), 7.55-7.61 (m,4H).

Example 141

A solution of Compound 22F (6.6 g, 31.27 mmol) in methanol (150 mL) wasstirred under HCl gas at room temperature for 6 h. It was quenched withwater (30 mL) and stirred at room temperature for 1 h. After removal ofsolvent, the residue was dissolved in ethyl acetate (200 mL), washedwith water (50 mL×3) and brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated to give Compound 141A.

A solution of Compound 141A (6.7 g, 27.46 mmol) and Dess-Martinperiodinane (14 g, 33 mmol) in DCM (50 mL) was stirred at roomtemperature for 2 h. After removal of solvent, the residue was dissolvedin ethyl acetate (200 mL), washed with water (50 mL×3) and brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give aresidue. The crude product was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, from 20% to 30% v/v) toafford Compound 141B.

A solution of Compound 141B (2.0 g, 8.26 mmol) in EtOH (20 mL) was addedpotassium carbonate (1.48 g, 10.7 mmol) and hydroxylamine hydrochloride(0.74 g, 10.7 mmol) at room temperature, then stirred at roomtemperature overnight. Then it was filtered and concentrated to obtainCompound 141C.

A mixture of Compound 141C (2.0 g, 7.78 mmol) and LiOH.H₂O (1.0 g, 23.3mmol) in THF/MeOH/H₂O (10/10/4 mL) was stirred at room temperature for 3h. The solution was concentrated to remove organic solvent, then it wasadjusted to PH 6 with 3 M HCl (5 mL), filtered and washed with PE (100mL), dried to obtain Compound 141D.

To a solution of Compound 141D (72 mg, 0.3 mmol) and Intermediate H (90mg, 0.3 mmol) in DMF was added EDCI.HCl (86 mg, 0.45 mmol), followed byHOBt (62 mg, 0.45 mmol). Then the reaction was stirred at roomtemperature for 15 hours. Then the reaction mixture was treated withwater (40 mL), extracted with DCM (100 mL×2), washed with brine (50 mL),dried over sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to furnish Compound 141. LC-MS (ESI) m/z: 508[M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 2.15-2.20 (m, 1H), 2.41-2.55 (m,1H), 3.15-3.27 (m, 2H), 3.65-3.90 (m, 2H), 4.12-4.15 (m, 3H), 4.24 (s,4H), 4.75-4.76 (d, J=2.8 Hz, 1H), 6.65-6.71 (m, 2H), 7.36-7.46 (m, 3H),7.64 (s, 1H), 7.75-7.82 (m, 3H).

Example 142

A mixture of Compound 141D (150 mg, 0.62 mmol), EDCI.HCl (178 mg, 0.93mmol), HOBt (126 mg, 0.92 mmol) and Intermediate G (230 mg, 0.7 mmol) inDMF (8 mL) was stirred at room temperature overnight. Then the reactionmixture was purified with prep-HPLC to provide Compound 142. LC-MS (ESI)m/z: 536.2 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 0.63-0.73 (m, 4H),1.95-2.09 (m, 4H), 2.65-3.14 (m, 7H), 3.43-3.47 (m, 1H), 3.55-3.58 (m,2H), 3.70-3.77 (m, 2H), 4.47-4.50 (m, 1H), 4.84-4.85 (d, J=2.4 Hz, 1H),7.25-7.32 (m, 3H), 7.40-7.45 (m, 3H), 7.74 (s, 1H), 7.76-7.80 (m, 3H).

Example 143

A mixture of Compound 141B (2.0 g, 8.26 mmol) and LiOH.H₂O (1.0 g, 24.8mmol) in THF/MeOH/H₂O (10/10/4 mL) was stirred at room temperature for 5h. The mixture was adjusted to pH 6 with aqueous HCl solution (6 N, 1.0mL). After removal of solvent the residue was dissolved in ethyl acetate(100 mL), washed with water (50 mL×2) and brine (30 mL), dried overanhydrous sodium sulfate, and concentrated to give a residue. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 10% to 30% v/v) to affordCompound 143A.

A mixture of Compound 143A (90 mg, 0.4 mmol), Intermediate C (118 mg,0.4 mmol), and HATU (228 mg, 0.6 mmol) in dichloromethane (10 mL) wasstirred at 30° C. for 15 h. Then it was treated with water (20 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuum and purified with prep-HPLC to furnishCompound 143. LC-MS (ESI) m/z: 506 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm) 1.77 (s, 2H), 1.93 (s, 2H), 2.87-2.96 (m, 2H), 3.00-3.10 (m, 4H),3.21-3.27 (m, 4H), 4.18-4.30 (m, 5H), 4.61 (s, 1H), 5.95 (s, 1H), 6.67(t, J=12 Hz, 2H), 7.36 (d, J=8 Hz, 1H), 7.40-7.47 (m, 2H), 7.67 (s, 1H),7.78-7.84 (m, 3H), 8.14 (d, J=12 Hz, 1H), 9.03 (s, 1H).

Example 144

A mixture of Compound 22J (0.1 g, 0.4 mmol), Intermediate F (0.11 g, 0.4mmol), DIPEA (0.10 g, 0.8 mmol), EDCI.HCl (0.11 g, 0.6 mmol) and HOBt(0.08 g, 0.6 mmol) in DCM (2 mL) was stirred at 25° C. for 16 h. Thenthe mixture was diluted with ethyl acetate (30 mL), washed with water(10 mL×2) and brine (10 mL), dried over sodium sulfate, concentrated,and purified with prep-HPLC to furnish Compound 144. LC-MS (ESI) m/z:497 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 2.15-2.22 (m, 2H), 2.41-2.71(m, 4H), 3.54-3.63 (m, 3H), 3.77-3.89 (m, 3H), 4.20-4.23 (m, 4H),4.39-4.42 (m, 1H), 4.85 (d, J=3.2 Hz, 1H), 6.77-6.79 (m, 1H), 6.84-6.90(m, 2H), 7.26-7.29 (m, 1H), 7.44-7.48 (m, 2H), 7.59 (s, 1H), 7.80-7.83(m, 3H).

Example 145

To a solution of Compound 143A (90 mg, 0.4 mmol) in dry dichloromethane(8 mL) and DMF (2 mL) was added HATU (228 mg, 0.6 mmol), followed byIntermediate H (90 mg, 0.3 mmol) in DMF. Then EDCI.HCl (86 mg, 0.45mmol) and HOBt (62 mg, 0.45 mmol) was added. The reaction was stirred atroom temperature for 15 hours, filtered, and evaporated to furnish thecrude product in DMF (3 mL). It was purified with prep-HPLC to furnishCompound 145. LC-MS (ESI) m/z: 493 [M+H]⁺; 1H-NMR (DMSO-d₆, 400 MHz) δ(ppm) 2.20-2.35 (m, 2H), 2.90-3.00 (m, 2H), 3.12-3.35 (m, 4H), 3.80-4.20(m, 5H), 4.25 (s, 4H), 4.62 (s, 1H), 5.96 (s, 1H), 6.65-6.74 (m, 2H),7.38-7.51 (m, 3H), 7.71 (s, 1H), 7.82-7.88 (m, 3H), 8.09-8.12 (d, J=9.6Hz, 1H), 9.35 (br, 1H).

Example 146

A mixture of Intermediate 0 (120 mg, 0.34 mmol), EDCI.HCl (98 mg, 0.51mmol), HOBt (69 mg, 0.51 mmol) and Compound 132D (120 mg, 0.34 mmol) inDCM (10 mL) was stirred h at 25° C. for 12. Then the mixture was washedwith saturated sodium bicarbonate (15 mL) and brine (15 mL), and driedover anhydrous sodium sulfate. After evaporation, the crude product waspurified with prep-HPLC to furnish Compound 146. LC-MS (ESI) m/z: 593[M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ (ppm) 1.63-1.70 (m, 2H), 1.78-1.84 (m,2H), 2.03 (m, 4H), 2.83 (m, 1H), 2.93 (m, 1H), 3.71-3.92 (m, 8H),4.17-4.22 (m, 1H), 4.37 (m, 1H), 5.00 (s, 1H), 6.48 (d, J=8.4 Hz, 1H),6.91 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 7.31 (d, J=9.2 Hz, 1H), 7.41 (dd,J=8.8, 2.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.76(m, 1H), 7.82-7.86 (m, 2H), 11.44 (s, 1H).

Example 147

A mixture of Compound 143A (152 mg, 0.67 mmol), HATU (456 mg, 1.2 mmol),DCM (16 mL) and Intermediate G (248 mg, 0.8 mmol) in DMF (6 mL) wasstirred at room temperature overnight. Then the reaction mixture wastreated with water (20 mL), extracted with DCM (50 mL×2), washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated.The crude product was purified with prep-HPLC to provide Compound 147.LC-MS (ESI) m/z: 521.3 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm)0.63-0.78 (m, 4H), 1.82-1.98 (m, 4H), 2.94-3.12 (m, 5H), 3.21-3.24 (m,1H), 3.46-3.49 (m, 3H), 3.83-3.86 (m, 2H), 4.31-4.36 (m, 1H), 4.74 (d,J=2.8 Hz, 1H), 6.01 (s, 1H), 7.21-7.24 (m, 1H), 7.30-7.40 (m, 3H),7.45-7.50 (m, 2H), 7.70 (s, 1H), 7.82-7.88 (m, 3H), 8.20 (d, J=9.6 Hz,1H), 9.38 (s, 1H).

Example 148

A mixture of Compound 143A (97 mg, 0.4 mmol), Intermediate C (118 mg,0.4 mmol), HOBt (81 mg, 0.6 mmol), and EDCI.HCl (115 mg, 0.6 mmol) inDMF (10 mL) was stirred at 30° C. for 8 h. The mixture was purified withprep-HPLC directly to furnish Compound 148. LC-MS (ESI) m/z: 522 [M+H]⁺;¹H-NMR (MeOD, 400 MHz) δ (ppm) 1.93 (s, 2H), 2.09 (s, 2H), 2.68-2.95 (m,4H), 3.04-3.17 (m, 2H), 3.40-3.44 (m, 1H), 3.54 (t, J=12 Hz, 2H), 3.69(s, 1H), 4.14-4.21 (m, 4H), 4.44-4.49 (m, 1H), 4.75 (s, 1H), 6.74 (d,J=12 Hz, 2H), 7.33 (d, J=8 Hz, 1H), 7.38-7.45 (m, 2H), 7.62 (s, 1H),7.70 (d, J=8 Hz, 0.5H), 7.70-7.85 (m, 3H).

Example 149

A mixture of Compound 133D (230 mg, 0.94 mmol), HATU (515 mg, 1.36mmol), and Intermediate G (324 mg, 1.05 mmol) in DCM (25 mL) was stirredat room temperature overnight. Then the reaction mixture was treatedwith water (20 mL), extracted with DCM (50 mL×2), washed with brine (50mL), dried over anhydrous sodium sulfate, and concentrated. The crudeproduct was purified with prep-HPLC to provide Compound 149. LC-MS (ESI)m/z: 537.2 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 0.69-0.83 (m, 4H),1.82-1.98 (m, 4H), 2.94-3.12 (m, 5H), 3.21-3.24 (m, 1H), 3.46-3.49 (m,3H), 2.04-2.08 (m, 3H), 2.19-2.22 (m, 2H), 3.23-3.33 (m, 1H), 3.58-3.75(m, 4H), 3.82-3.86 (m, 2H), 4.70-4.73 (m, 2H), 5.01 (s, 1H), 7.23-7.27(m, 2H), 7.39 (d, J=0.8 Hz, 1H), 7.64-7.70 (m, 4H), 7.73-7.76 (m, 2H).

Example 150

A mixture of Compound 133D (195 mg, 0.8 mmol), Intermediate H (225 mg,0.8 mmol), and HATU (456 mg, 1.2 mmol) in dichloromethane (20 mL) wasstirred at 30° C. for 8 h. Then it was treated with water (20 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuum and purified with prep-HPLC to furnishCompound 150. LC-MS (ESI) m/z: 509 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ(ppm) 2.47 (s, 2H), 3.46-3.65 (m, 2H), 4.12-4.34 (m, 9H), 4.89 (s, 1H),6.69 (d, J=12 Hz, 2H), 7.12 (t, J=8 Hz, 2H), 7.55 (t, J=8 Hz, 4H), 7.90(d, J=8 Hz, 2H).

Example 151

To a solution of Compound 132B (262 mg, 1 mmol) in ethanol/water (16 mL,15/1 v/v) was added LiOH H₂O (84 mg, 2 mmol). The mixture was stirred atroom temperature overnight. After the completion of the reaction, themixture was adjusted to pH 2 with aqueous HCl solution (3 N, 40 mL) andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (200 mL), dried over anhydrous sodium sulfate, andconcentrated to yield the Compound 151A.

To a solution of Compound 151A (170 mg, 0.73 mmol) and Intermediate C(216 mg, 0.73 mmol) in dichloromethane (6 mL) was added HATU (414 mg,1.09 mmol) at 25° C. Then the reaction was stirred at 25° C. for 15hours. Then the reaction mixture was treated with water (40 mL),extracted with DCM (10 mL×2), washed with brine (10 mL), dried oversodium sulfate, and concentrated. The crude product was purified withprep-HPLC to furnish Compound 151. LC-MS (ESI) m/z: 513 [M+H]⁺; ¹H-NMR(MeOD, 400 MHz) δ (ppm) 2.05-2.07 (m, 2H), 2.22-2.25 (m, 1H), 3.20-3.22(m, 2H), 3.58-3.95 (m, 4H), 4.05-4.24 (m, 4H), 4.56-4.59 (d, J=10.4 Hz,1H), 4.95-4.96 (d, J=2.4 Hz, 1H), 6.75-6.81 (m, 2H), 7.52-7.55 (dd,J=2.0 Hz, J=8.4 Hz, 1H), 7.79-7.97 (m, 4H), 8.49 (s, 1H).

Example 152

A mixture of Compound 133D (82.5 mg, 0.34 mmol), HATU (193.8 mg, 0.51mmol) and Intermediate O (120 mg, 0.34 mmol) in DCM (10 mL) was stirredfor 12 h at 25° C. Then the mixture was washed with water (15 mL) andbrine (15 mL), and dried over anhydrous sodium sulfate. Afterevaporation, the crude product was purified with prep-HPLC to furnishCompound 152. LC-MS (ESI) m/z: 581 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ(ppm) 1.68-1.75 (s, 2H), 1.88-1.90 (s, 2H), 2.08-2.15 (m, 4H), 3.14-3.26(m, 4H), 3.47-3.52 (m, 2H), 3.87-3.91 (m, 4H), 4.41-4.45 (m, 1H),4.55-4.57 (m, 1H), 5.08 (s, 1H), 6.85 (d, J=17.2 Hz, 1H), 7.10-7.14 (m,2H), 7.20-7.22 (m, 1H), 7.40 (s, 1H), 7.50-7.54 (m, 4H), 7.90-7.94 (m,3H), 9.01 (s, 1H).

Example 153

A mixture of 149 (36 mg, 0.07 mmol) and hydroxylamine hydrochloride (69mg, 1.0 mmol) in methanol (6 mL) was stirred at 50° C. for 16 hours.Then the reaction mixture was purified with prep-HPLC to provideCompound 153. LC-MS (ESI) m/z: 552.1 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ(ppm) 0.72-0.83 (m, 4H), 1.82-1.98 (m, 4H), 2.94-3.12 (m, 5H), 3.21-3.24(m, 1H), 3.46-3.49 (m, 3H), 2.04-2.08 (m, 3H), 2.04-2.21 (m, 4H),3.20-3.33 (m, 2H), 3.59-3.89 (m, 5H), 4.83-4.87 (m, 1H), 5.03 (d, J=2.4Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 7.38-7.42 (m, 2H), 7.48-7.52 (m, 3H),7.66-7.69 (m, 2H).

Example 154

A mixture of Intermediate I (145 mg, 0.49 mmol), HATU (278 mg, 0.73mmol), and Compound 90A (100 mg, 0.406 mmol) in DMF (3 mL) and DCM (6mL) was stirred at 25° C. overnight. Then the reaction mixture wasconcentrated to remove DCM. The residue was purified with prep-HPLC toprovide Compound 154. LC-MS (ESI) m/z: 525 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz) δ (ppm) 0.61-0.65 (m, 2H), 0.76-0.81 (m, 2H), 2.16-2.25 (m, 1H),2.31-2.39 (m, 1H), 2.93-2.98 (m, 2H), 3.05-3.14 (m, 1H), 3.20-3.42 (m,3H), 3.84-3.88 (m, 1H), 3.92-3.99 (m, 2H), 4.05-4.18 (m, 3H), 4.69 (s,1H), 5.97 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.31-7.33 (m, 2H), 7.39-7.45(m, 2H), 7.66 (d, J=12.8 Hz, 1H), 7.75 (s, 1H), 7.84 (d, J=8.8 Hz, 1H),7.91-7.94 (m, 1H), 8.13 (d, J=9.6 Hz, 1H), 9.34 (s, 1H).

Example 155

A mixture of 150 (90 mg, 0.18 mmol) and hydroxylamine hydrochloride (248mg, 3.54 mmol) in MeOH (10 mL) was stirred at room temperature for 4 h.Then it was purified with prep-HPLC directly to provide Compound 155.LC-MS (ESI) m/z: 523 [M+H]*; 1H-NMR (MeOD, 400 MHz) δ (ppm) 2.44 (s,1H), 2.56-2.66 (m, 1H), 3.53-3.67 (m, 2H), 4.18-4.45 (m, 9H), 4.45 (s,0.5H), 4.81 (s, 0.5H), 6.77-6.83 (m, 2H), 7.17-7.23 (m, 3H), 7.40-7.69(m, 5H).

Example 156

To a solution of Compound 156A (100 mg, 0.38 mmol) in THF/water (8 mL,15:1, v/v) was added LiOH.H₂O (25 mg, 0.58 mmol). The mixture wasstirred at −10° C. for 1 h. After the reaction was completed, it wasadjusted to pH to 6 with 3 N HCl and extracted with ethyl acetate (15mL×3). The combined organic layers were concentrated in vacuum withoutdryness to provide the desired product Compound 156B.

To a solution of Compound 156B (85 mg, 0.36 mmol) and Intermediate C(108 mg, 0.36 mmol) in dichloromethane (3 mL) was added HATU (207 mg,0.54 mmol) at 25° C. Then the reaction was stirred at 25° C. for 15hours. Then the reaction mixture was treated with water (20 mL),extracted with DCM (10 mL×2), washed with brine (10 mL), dried oversodium sulfate, and concentrated. The crude product was purified withprep-HPLC to furnish Compound 156. LC-MS (ESI) m/z: 513 [M+H]⁺; ¹H-NMR(MeOD, 400 MHz) δ (ppm) 2.05-2.17 (m, 4H), 3.11-4.12 (m, 6H), 4.17-4.31(m, 4H), 4.55-4.57 (m, 1H), 4.95 (d, J=2.0 Hz, 1H), 6.75-6.83 (m, 2H),7.48-7.56 (m, 2H), 7.75-7.98 (m, 4H), 8.55 (d, J=9.2 Hz, 1H).

Example 157

To a solution of Compound 140B (67 mg, 0.25 mmol), Intermediate H (78mg, 0.26 mmol), and EDCI.HCl (72 mg, 0.375 mmol) in dichloromethane (10mL) was added HOBt (51 mg, 0.375 mmol) at 19° C., then the reaction wasstirred at 19° C. for 4 h. Then it was treated with water (20 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuum and purified with prep-HPLC to furnishCompound 157. LC-MS (ESI) m/z: 531 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ(ppm) 2.29-2.38 (m, 2H), 2.72 (br, 1H), 4.08-4.37 (m, 10H), 4.91 (s,1H), 6.54-6.66 (m, 2H), 7.12-7.17 (m, 2H), 7.41 (d, J=8.4 Hz, 2H),7.53-7.58 (m, 4H).

Example 158

To a solution of 151 (40 mg, 0.064 mmol) in MeOH (15 mL) was addedhydroxylamine hydrochloride (90 mg, 1.28 mmol) at 30° C., then thereaction was stirred at 55° C. for 4 h. Then it was purified withprep-HPLC to furnish Compound 158. LC-MS (ESI) m/z: 528 [M+H]⁺; ¹H-NMR(MeOD, 400 MHz) δ (ppm) 2.03-2.23 (m, 4H), 3.28-3.34 (m, 1H), 3.50-3.92(m, 4H), 4.13-4.32 (m, 4H), 4.84-4.93 (m, 1H), 6.81-6.90 (m, 2H),7.50-7.53 (m, 2H), 7.72-7.92 (m, 4H).

Example 159

A mixture of Compound 140B (172 mg, 0.64 mmol), EDCI.HCl (186 mg, 0.97mmol), HOBt (132 mg, 0.97 mmol) and Intermediate G (200 mg, 0.64 mmol)in DCM (15 mL) was stirred at room temperature overnight. Then thereaction mixture was treated with water (20 mL), extracted with DCM (50mL×2), washed with brine (50 mL), dried over anhydrous sodium sulfate,and concentrated. The crude product was purified with prep-HPLC toprovide Compound 159. LC-MS (ESI) m/z: 559.2 [M+H]⁺; ¹H-NMR (MeOD, 400MHz) δ (ppm) 0.49-0.61 (m, 4H), 2.03-2.04 (m, 4H), 3.15-3.30 (m, 2H),3.53-3.81 (m, 5H), 4.63 (d, J 10.4 Hz, 1H), 7.04 (d, J 8.4 Hz, 1H),7.11-7.13 (m, 1H), 7.21-7.25 (m, 2H), 7.34-7.36 (m, 3H), 7.63 (d, J=8.0Hz, 2H), 7.71-7.75 (m, 2H).

Example 160

A mixture of Compound 140B (0.10 g, 0.4 mmol), Intermediate A (0.10 g,0.4 mmol), DIPEA (0.1 g, 0.8 mmol), EDCI.HCl (0.10 g, 0.6 mmol) and HOBt(0.08 g, 0.6 mmol) in DCM (2 mL) was stirred at 25° C. for 16 h. Thenthe mixture was diluted with ethyl acetate (30 mL), washed with water(10 mL×2) and brine (10 mL), dried over sodium sulfate, concentrated,and purified with prep-HPLC to furnish Compound 160. LC-MS (ESI) m/z:527 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) & (ppm) 2.01-2.25 (m, 4H), 3.15-3.22(m, 2H), 3.52-3.66 (m, 3H), 3.77-3.79 (m, 1H), 4.07 (s, 4H), 4.56-4.58(m, 1H), 4.83 (d, J=3.2 Hz, 1H), 6.63-6.65 (m, 1H), 6.72-6.77 (m, 2H),7.20-7.25 (m, 2H), 7.43-7.45 (m, 2H), 7.65-7.73 (m, 4H).

Example 161

A mixture of Compound 140B (0.10 g, 0.4 mmol), Intermediate F (0.10 g,0.4 mmol), DIPEA (0.1 g, 0.8 mmol), EDCI.HCl (0.10 g, 0.6 mmol) and HOBt(0.08 g, 0.6 mmol) in DCM (2 mL) was stirred at 25° C. for 16 h. Thenthe mixture was diluted with ethyl acetate (30 mL), washed with water(10 mL×2) and brine (10 mL), dried over sodium sulfate, concentrated,and purified with prep-HPLC to furnish Compound 161. LC-MS (ESI) m/z:513 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 2.38-2.62 (m, 2H), 3.53-3.56(m, 2H), 4.08 (s, 4H), 4.19-4.26 (m, 4H), 4.36-4.38 (m, 1H), 4.80 (d,J=3.2 Hz, 1H), 6.64-6.77 (m, 3H), 7.21-7.25 (m, 2H), 7.41-7.43 (m, 2H),7.65-7.73 (m, 4H).

Example 162

A mixture of Compound 140B (172 mg, 0.64 mmol), EDCI.HCl (186 mg, 0.97mmol), HOBt (132 mg, 0.97 mmol) and Intermediate I (191 mg, 0.64 mmol)in DCM (15 mL) was stirred at room temperature overnight. Then thereaction mixture was treated with water (20 mL), extracted with DCM (50mL×2), washed with brine (50 mL), dried over anhydrous sodium sulfate,and concentrated. The crude product was purified with prep-HPLC toprovide Compound 162. LC-MS (ESI) m/z: 545.1 [M+H]⁺; ¹H-NMR (MeOD, 400MHz) δ (ppm) 0.49-0.64 (m, 4H), 2.43-2.61 (m, 2H), 3.54-3.62 (m, 3H),4.21-4.47 (m, 6H), 7.06 (d, J=8.4 Hz, 1H), 7.11-7.13 (m, 1H), 7.21-7.25(m, 2H), 7.32-7.36 (m, 3H), 7.61-7.64 (m, 3H), 7.71-7.74 (m, 2H).

Example 163

A mixture of Intermediate 0 (120 mg, 0.34 mmol), EDCI.HCl (98 mg, 0.51mmol), HOBt (69 mg, 0.51 mmol) and Compound 140B (90 mg, 0.34 mmol) inDCM (10 mL) was stirred for 12 h at 25° C. Then the mixture was washedwith saturated sodium bicarbonate (15 mL) and brine (15 mL), and driedover anhydrous sodium sulfate. After evaporation, the crude product waspurified with prep-HPLC to furnish Compound 163. LC-MS (ESI) m/z: 603[M+H]⁺; 1H-NMR (CDCl₃, 400 MHz) δ (ppm) 1.65-1.75 (m, 2H), 1.85-1.89 (m,2H), 2.13 (m, 4H), 2.91-3.03 (m, 2H), 3.49-3.54 (m, 4H), 3.76-3.94 (m,4H), 4.40 (m, 2H), 5.16 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.07-7.15 (m,3H), 7.31-7.37 (m, 3H), 7.50-7.57 (m, 4H), 7.69 (d, J=4.8 Hz, 1H), 11.80(s, 1H).

Example 164

A solution of Compound 141D (150 mg, 0.60 mmol), Intermediate I (182 mg,0.6 mmol), EDCI.HCl (171 mg, 0.9 mmol), HOBt (121 mg, 0.9 mmol), andDIPEA (0.2 mL, 2.40 mmol) in DCM (10 mL) and DMF (10 mL) was stirred atroom temperature overnight under nitrogen. Then it was evaporated andpurified with prep-HPLC to furnish Compound 164. LC-MS (ESI) m/z: 522[M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 0.64-0.75 (m, 4H), 2.21-2.48 (m,2H), 2.64-2.80 (m, 2H), 2.82-2.98 (m, 2H), 3.38-3.55 (m, 2H), 3.73-3.80(m, 1H), 3.80-3.89 (m, 2H), 4.06-4.19 (m, 2H), 4.21-4.32 (m, 1H),4.80-4.83 (m, 1H), 7.22-7.27 (m, 1H), 7.30-7.34 (m, 2H), 7.38-7.47 (m,3H), 7.58-7.62 (m, 1H), 7.74-7.83 (m, 3H).

Example 165

To a cooled solution of Compound 165A (10 g, 67 mmol),2,6-dimethylpyridine (10.8 g, 101 mmol), and DMAP (1.65 mmol, 13 mmol)in DCM (100 mL) was added dropwise Tf₂O (30.5 g, 108 mmol) at 0° C. Theresulting mixture was stirred at room temperature overnight, dilutedwith DCM, and washed with diluted HCl. The mixture was extracted withDCM (50 mL×2), washed with sat. sodium bicarbonate (50 mL) and brine (50mL), dried over anhydrous sodium sulfate, concentrated, and purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 5% v/v) to afford Compound 165B.

A mixture of Compound 165B (18 g, 64 mmol), methyl acrylate (16.6 g, 193mmol), Pd(PPh₃)₂Cl₂ (2.26 g, 3.2 mmol), and K₂CO₃ (22 g, 161 mmol) inDMF (100 mL) was stirred at 100° C. for 12 h. The mixture was cooled toroom temperature, and filtered. The filtrate was treated with water (50mL), extracted with DCM (100 mL×2), washed with water (100 mL×3) andbrine (100 mL), dried over anhydrous sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, 5% v/v) to afford Compound 165C.

To a solution of Compound 165C (11 g, 51 mmol) in methanol (150 mL) wasadded Pd/C (1.1 g). The resulting mixture was stirred at roomtemperature for 12 h under H₂ and filtered. The filtrate wasconcentrated to give a crude Compound 165D.

To a solution of AlLiH₄ (1.2 g, 31 mmol) in THF (25 mL) was addedCompound 165D (6.76 g, 31 mmol) in THF (20 mL) dropwise under nitrogenat −78° C. The mixture was stirred at −78° C. for 2 h and quenched withNa₂SO₄.10H₂O. The filtrate was concentrated to afford the crude Compound165E.

To a solution of Compound 165E (5.2 g, 27 mmol) in DCM (100 mL) wasadded Dess-Martin periodinane (13.9 g, 33 mmol) at 0° C. The resultingmixture was stirred at room temperature for 2 h and filtered. Thefiltrate was concentrated and the resulting residue was purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, 5% v/v) to afford Compound 165F.

Compound 165F (4 g, 22 mmol) was added to a solution of Na₂S₂O (4.11 g,22 mmol) in water (150 mL). The resultant mixture was stirred for 2 h atroom temperature, and NaCN (2.1 g, 43 mmol) was added. After stirringfor 15 h, the mixture was diluted with ethyl acetate (50 mL), extractedwith ethyl acetate (100 mL×2), washed with sat. sodium bicarbonate (100mL×2) and brine (100 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 165G.

To a solution of Compound 165G (4.4 g, 20 mmol) in ethanol (50 mL) at 0°C. was bubbled a gentle stream of HCl gas (dried over con. H₂SO₄) for 5h. The mixture was treated with water slowly at 0° C. and stirred atroom temperature for 2 h. The mixture was extracted with DCM (100 mL×2),washed with brine (100 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 165H.

To a solution of Compound 165H (2 g, 7.6 mmol) in DCM (20 mL) was addedDess-Martin periodinane (3.88 g, 9.1 mmol). The mixture was stirred atroom temperature for 2 h and filtered. The filtrate was concentrated andthe resulting residue was purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, 10% v/v) to affordCompound 1651.

To a solution of Compound 1651 (1.7 g, 6.5 mmol) in DCM (20 mL) wasadded DAST (5.3 g, 33 mmol). The mixture was stirred at room temperaturefor 12 h and poured into ice water. The mixture was extracted with DCM(50 mL×2), washed with brine (50 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, 10% v/v) to affordCompound 165J.

To a solution of Compound 165J (1.7 g, 6.0 mmol) in THF (50 mL) wasadded LiOH.H₂O (758 mg, 18 mmol) in water (5 mL). The resulting mixturewas stirred at room temperature for 2 h and evaporated to removesolvent. The mixture was treated with water (50 mL), adjusted to pH 2with diluted HCl, extracted with ethyl acetate (50 mL×2), washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated toafford the Compound 165K.

A mixture of Compound 165K (164 mg, 0.65 mmol), Intermediate A (150 mg,0.54 mmol), EDCI.HCl (155 mg, 0.81 mmol), and HOBt (110 mg, 0.81 mmol)in DCM (10 mL) was stirred at 25° C. overnight. Then the reactionmixture was concentrated to remove DCM. The residue was purified withprep-HPLC to provide Compound 165. LC-MS (ESI) m/z: 515 [M+H]⁺; ¹H-NMR(CDCl₃, 400 MHz) δ (ppm) 1.77 (s, 4H), 2.11-2.13 (m, 5H), 2.20-2.29 (m,1H), 2.72 (s, 4H), 2.87 (s, 3H), 3.03 (s, 1H), 3.44-3.46 (m, 2H), 3.83(s, 2H), 3.98-4.05 (m, 4H), 4.42-4.44 (m, 1H), 5.08 (s, 1H), 6.78-6.82(m, 4H), 6.87 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H),11.76 (s, 1H).

Example 166

A mixture of Intermediate G (200 mg, 0.64 mmol), Compound 165K (164 mg,0.64 mmol), EDCI.HCl (188 mg, 0.97 mmol), and HOBt (131 mg, 0.97 mmol)in DCM (10 mL) was stirred at 25° C. overnight. Then the reactionmixture was concentrated to remove DCM. The residue was purified withprep-HPLC to provide Compound 165. LC-MS (ESI) m/z: 547 [M+H]⁺; 1H-NMR(CDCl₃, 400 MHz) G (ppm) 0.63-0.69 (m, 4H), 1.77 (s, 4H), 2.14-2.16 (m,5H), 2.33-2.40 (m, 1H), 2.71 (s, 4H), 2.91-2.93 (m, 1H), 3.04 (s, 1H),3.50 (s, 5H), 3.82 (s, 2H), 4.47-4.48 (m, 1H), 5.13 (s, 1H), 6.75-6.78(m, 2H), 6.95 (d, J=7.6 Hz, 1H), 7.16-7.21 (m, 2H), 7.36 (s, 1H), 7.53(d, J=8.0 Hz, 1H), 11.60 (s, 1H).

Example 167

A mixture of Intermediate C (200 mg, 0.67 mmol), Compound 165K (172 mg,0.67 mmol), EDCI.HCl (197 mg, 1.01 mmol), and HOBt (136 mg, 1.01 mmol)in DCM (10 mL) was stirred at 25° C. overnight. Then the reactionmixture was concentrated to remove DCM. The residue was purified withprep-HPLC to provide Compound 167. LC-MS (ESI) m/z: 533 [M+H]⁺; 1H-NMR(CDCl₃, 400 MHz) δ (ppm) 1.75-1.78 (m, 4H), 2.15-2.21 (m, 6H), 2.38-2.44(m, 1H), 2.71 (s, 4H), 2.91 (s, 1H), 3.05-3.13 (m, 3H), 3.48 (s, 2H),3.83 (s, 2H), 4.00-4.06 (m, 3H), 4.44-4.45 (m, 1H), 5.07 (s, 1H),6.67-6.72 (m, 2H), 6.78-6.82 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.45 (d,J=8.4 Hz, 1H), 11.70 (s, 1H).

Example 168

To a solution of Intermediate V (100 mg, 0.29 mmol) and Compound 11E (72mg, 0.29 mmol) in DMF (10 mL) was added EDCI.HCl (84 mg, 0.44 mmol) andHOBt (59 mg, 0.44 mmol) under nitrogen. The mixture was stirred at 25°C. overnight. TLC and LC-MS showed the starting material was consumedcompletely, sat. sodium bicarbonate (5 mL) was added to the mixture andthen extracted with EA (50 mL×3). The combined organic layers werewashed with water (5 mL×3) and brine (5 mL), and dried over anhydroussodium sulfate, and concentrated to provide the crude product. The crudeproduct was purified with prep-HPLC to provide Compound 168. LC-MS (ESI)m/z: 571 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 1.31 (s, 6H), 1.98-2.00(m, 2H), 2.14-2.15 (m, 2H), 3.15-3.23 (m, 2H), 3.59-3.67 (m, 5H),3.72-3.75 (m, 1H), 4.60-4.62 (m, 1H), 4.90 (d, J=2.4 Hz, 1H), 6.72 (d,J=8.4 Hz, 1H), 6.74 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.39-7.41 (m, 2H),7.53 (d, J=9.2, 1H), 7.68 (d, J=2.0 Hz, 1H).

Example 169

A mixture of 122 (40.8 mg, 0.08 mmol), hydroxylamine hydrochloride (76mg, 1.1 mmol) and methanol (9 mL) was stirred at 50° C. for overnight.Then the mixture was purified with prep-HPLC to provide Compound 169.LC-MS (ESI) m/z: 518.1 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 0.75-0.85(m, 4H), 2.15-2.29 (m, 2H), 3.58-3.69 (m, 2H), 3.83-3.86 (m, 1H),4.25-4.42 (m, 4H), 4.65-4.67 (m, 1H), 4.99 (d, J=2.0 Hz, 1H), 5.86 (s,1H), 7.32-7.35 (m, 1H), 7.38 (s, 2H), 7.44-7.46 (d, J=8.8 Hz, 1H),7.52-7.54 (m, 2H).

Example 170

A solution of Compound 143A (114 mg, 0.5 mmol), Intermediate I (148 mg,0.5 mmol), and HATU (684 mg, 0.9 mmol) in DCM (16 mL) and DMF (6 mL) wasstirred at room temperature overnight under nitrogen. Then it wasevaporated and purified with prep-HPLC to furnish Compound 170. LC-MS(ESI) m/z: 507 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ (ppm) 0.10-0.90 (m, 4H),1.77-2.05 (m, 2H), 2.05-2.43 (m, 3H), 2.85-3.21 (m, 2H), 3.45-3.76 (m,2H), 4.08-4.41 (m, 5H), 4.88 (m, 1H), 7.12-7.14 (m, 2H), 7.21-7.51 (m,4H), 7.65-7.87 (m, 4H).

Example 171

A solution of Intermediate I (150 mg, 0.60 mmol), Compound 22J (148 mg,0.5 mmol), EDCI.HCl (143 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), andDIPEA (0.1 mL, 1.20 mmol) in DCM (20 mL) was stirred at room temperatureovernight under nitrogen. Then it was evaporated, and purified withprep-HPLC to furnish a mixture (100 mg, yield 38%) as a white solid,then the mixture was further separated with chiral HPLC (co-solvent:MeOH (0.5% DEA), column OZ-H (250*4.6 mm 5 um)) and prep-HPLC to provideCompound 171. LC-MS (ESI) m/z: 529 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ(ppm) 0.29-0.44 (m, 4H), 2.11-2.17 (m, 2H), 2.37-2.41 (m, 2H), 2.57-2.65(m, 2H), 3.26-3.27 (m, 1H), 3.57-3.60 (m, 2H), 4.19-4.32 (m, 4H),4.45-4.47 (m, 1H), 4.92-4.93 (m, 1H), 7.17-7.19 (m, 1H), 7.23-7.25 (m,1H), 7.29-7.32 (m, 1H), 7.43-7.49 (m, 3H), 7.55 (s, 1H), 7.79-7.83 (m,3H).

Example 172

A mixture of Compound 151A (137 mg, 0.59 mmol), HATU (445 mg, 1.17mmol), DMF (4 mL), and Intermediate G (218 mg, 0.70 mmol) in DCM (16 mL)was stirred at room temperature overnight. The reaction mixture wastreated with water (20 mL), extracted with DCM (50 mL×2), washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated.The crude product was purified with prep-HPLC to afford Compound 172.LC-MS (ESI) m/z: 527 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.54-0.79(m, 4H), 2.04-2.22 (m, 5H), 3.23-3.26 (m, 1H), 3.58-3.82 (m, 6H),4.70-4.73 (m, 1H), 4.99 (d, J=2.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H),7.37-7.41 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.57-7.59 (m, 1H), 7.88-7.93(m, 3H), 7.99 (d, J=1.2 Hz, 1H), 8.29 (s, 1H).

Example 173

A mixture of 172 (40.8 mg, 0.08 mmol), hydroxylamine hydrochloride (76mg, 1.1 mmol) and methanol (9 mL) was stirred at 50° C. overnight. Thenthe mixture was purified with prep-HPLC to provide Compound 173. LC-MS(ESI) m/z: 542.1 [M+H]⁺; 1H-NMR (MeOD, 400 MHz) δ (ppm) 0.69-0.84 (m,4H), 2.02-2.22 (m, 4H), 3.21-3.29 (m, 1H), 3.62-3.80 (m, 5H), 4.70-4.73(m, 1H), 5.01 (d, J=2.8 Hz, 1H), 7.32-7.34 (m, 1H), 7.39-7.43 (m, 1H),7.45-7.49 (m, 1H), 7.51-7.53 (m, 1H), 7.63-7.85 (m, 3H), 7.88-7.90 (m,1H).

Example 174

To a stirred solution of Compound 174A (2.0 g, 15.4 mmol) in dioxane (60mL) and water (20 mL) was added Pd(PPh₃)₂Cl₂ (1.08 g, 1.54 mmol),Compound 174B (3.0 g, 18.5 mmol) and Na₂CO₃ (6.53 g, 61.6 mmol) undernitrogen. The mixture was stirred at 80° C. overnight. After thereaction was completed, it was evaporated to remove the solvent. Theresidue was diluted with EA (200 mL), washed with water (5 mL) and brine(5 mL), and dried over anhydrous sodium sulfate. The crude product waspurified with flash column chromatography on silica gel (petroleum inethyl acetate, 3% v/v) to furnish Compound 174C.

To a solution of Compound 174C (890 mg, 5.0 mmol) in dry THF (50 mL) wasadded dropwise LDA (2.0 M, 3.0 mL, 6.0 mmol) under nitrogen at −70° C.After stirring for 30 min., diethyl oxalate (2.19 g, 15.0 mmol) wasadded as soon as possible. Then the mixture was stirred at −70° C. forabout 1 h. Then the mixture was quenched with sat. NH₄Cl (10 mL),extracted with ethyl acetate (50 mL×3), washed with water (5 mL) andbrine (5 mL), and dried over sodium sulfate. The crude product waspurified with flash column chromatography on silica gel (petroleum inethyl acetate, 10% v/v) to furnish Compound 174D.

To a solution of Compound 174D (500 mg, 1.8 mmol) in THF (6 mL) wasadded dropwise a solution of LiOH.H₂O (83 mg, 1.98 mmol) in water (1.5mL) slowly at −30° C. Then the mixture was stirred at −30° C. about 0.5h. It was adjusted to pH 3 with HCl (1 N), and extracted with DCM (100mL×3). The organic phase was dried over sodium sulfate, filtered andconcentrated to furnish the Compound 174E.

To a solution of Compound 174E (360 mg, 1.44 mmol) in DMF (15 mL) wasadded HATU (821 mg, 2.16 mmol). After stirring for two hours at 25° C.,Intermediate A (400 mg, 1.44 mmol) was added and the resultant mixturewas stirred overnight at 25° C. TLC and LC-MS showed the startingmaterial was consumed completely, and sat. sodium bicarbonate (5 mL) wasadded to the mixture and then extracted with EA (50 mL×3). The combinedorganic layers were washed with water (5 mL×3) and brine (5 mL), anddried over anhydrous sodium sulfate, and concentrated to provide thecrude product. The crude product was purified with prep-HPLC to provideCompound 174. LC-MS (ESI) m/z: 511 [M+H]⁺; ¹H-NMR (MeOD, 400 MHz) δ(ppm) 1.97-2.02 (m, 2H), 2.13-2.17 (m, 2H), 3.16-3.23 (m, 2H), 3.40-3.44(m, 1H), 3.60-3.70 (m, 2H), 3.76-3.82 (m, 1H), 4.11-4.18 (m, 4H),4.46-4.51 (m, 1H), 4.82 (d, J=3.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.85(dd, J=2.0, 8.4 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 7.21 (t, J=8.8 Hz, 2H),7.49 (d, J=4.4 Hz, 1H), 7.78-7.82 (m, 2H), 8.15 (d, J=4.4 Hz, 1H).

Example 175

To a solution of Compound 175A (5.12 g, 20 mmol) in dioxane (75 mL) wasadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.10g, 24 mmol), Pd(dppf)Cl₂ (902 mg, 1 mmol) and KOAc (5.9 g, 60 mmol). Thereaction mixture was heated to 90° C. for 2.5 h, then the solution wascooled to r.t and filtered. The filtrate was concentrated to offer thecrude product. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v)to offer Compound 175B.

A mixture of Compound 175B (730 mg, 2.4 mmol), Compound 175C (350 mg, 2mmol), Pd(PPh₃)₄ (116 mg, 0.1 mmol) and K₃PO₄ (1.27 g, 6 mmol) intoluene (20 mL) was heated to reflux, stirred for 3 h and filtered. Thefiltrate was concentrated to offer the crude product. The crude productwas purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 20% v/v) to offer Compound 175D.

To a solution of Compound 175D (119 mg, 0.44 mmol) in THF/water (11 mL,15:1, v/v) was added LiOH.H₂O (28 mg, 0.66 mmol). The mixture wasstirred at −10° C. for 1 h. After the reaction, it was adjusted to pH 6with 3 N HCl and extracted with ethyl acetate (20 mL×3). The combinedorganic layers were concentrated in vacuum without dryness to offer thecrude product Compound 175E.

A mixture of Compound 175E (100 mg, 0.408 mmol), Intermediate G (124 mg,0.408 mmol) and HATU (233 mg, 0.612 mmol) in dichloromethane (2 mL) andDMF (2 mL) was stirred at 25° C. for 15 h. Then it was treated withwater (20 mL), extracted with dichloromethane (20 mL×3), dried overanhydrous sodium sulfate, concentrated in vacuum and purified withprep-HPLC to obtain Compound 175. LC-MS (m/z): 538 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) δ (ppm) 0.79-0.84 (m, 4H), 2.11-2.14 (m, 4H), 3.01-3.19(m, 2H), 3.42-3.90 (m, 5H), 4.55-4.57 (m, 1H), 4.79 (m, 1H), 7.28-7.32(m, 2H), 7.41-7.62 (m, 2H), 7.82-7.86 (m, 1H), 7.95-8.01 (m, 4H), 8.57(d, J=3.2 Hz, 1H).

Example 176

A mixture of Compound 175E (98 mg, 0.4 mmol), Intermediate C (118 mg,0.4 mmol), and HATU (228 mg, 0.6 mmol) in DMF (10 mL) was stirred at 30°C. for 8 h. Then it was treated with water (20 mL), extracted withdichloromethane (20 mL×3), dried over anhydrous sodium sulfate,concentrated in vacuum and purified with prep-HPLC to obtain Compound176. LC-MS (m/z): 524 [M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) δ (ppm) 2.04 (s,2H), 2.19 (s, 2H), 3.18-3.30 (m, 2H), 3.48-3.57 (m, 1H), 3.65-3.74 (m,2H), 3.78-3.84 (m, 1H), 4.19-4.34 (m, 5H), 4.65 (d, J=8 Hz, 1H), 6.81(d, J=12 Hz, 1H), 7.69-7.76 (m, 1H), 7.90 (d, J=8 Hz, 2H), 8.02-8.05 (m,1H), 8.11 (d, J=8 Hz, 2H), 8.60 (s, 1H).

Example 177

A mixture of 152 (30 mg, 0.04 mmol) and NH₂OH.HCl (27.6 mg, 0.4 mmol) inMeOH (3 mL) was stirred for 4 h at 55° C. After filtration, the filtratewas purified with prep-HPLC to furnish Compound 177. LC-MS (m/z): 596[M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) major characteristic peaks: δ (ppm)172-1.81 (m, 2H), 1.98-2.08 (m, 2H), 3.30 (m, 1H), 3.51-3.74 (m, 4H),3.88-3.99 (m, 4H), 4.65-4.70 (m, 1H), 5.03 (s, 1H), 7.09-7.11 (m, 2H),7.15-7.23 (m, 3H), 7.35 (dd, J=8.4, 2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H),7.55 (d, J=2.0 Hz, 1H), 7.66-7.70 (m, 2H).

Example 178

To a solution of Compound 178A (2.56 g, 10 mmol) in dry dichloromethane(50 mL) was added DAST (3.30 mL, 25 mmol). Then the mixture was stirredat 25° C. for 14 h. After the reaction, dichloromethane (25 mL) wasadded, then the organic layer was washed with water (50 mL), followed byaddition of aq. sodium bicarbonate (30 mL) and brine (50 mL), dried oversodium sulfate and concentrated to offer the crude product. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, 20% v/v) to offer Compound 178B.

To a solution of Compound 178B (2.58 g, 9.3 mmol) in dioxane (45 mL) wasadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.82g, 11.1 mmol), Pd(dppf)Cl₂ (409 mg, 0.5 mmol) and KOAc (2.72 g, 27.8mmol). The reaction mixture was heated to 90° C. for 2.5 h, then thesolution was cooled to r.t and filtered. The filtrate was concentratedto offer the crude product. The crude product was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,10% v/v) to offer Compound 178C.

To a solution of Compound 178C (717 mg, 2.2 mmol),2-bromo-5-fluoropyridine (350 mg, 2 mmol), and K₃CO₃ (828 mg, 6 mmol) indioxane (20 mL) and water (2 mL) was added Pd(dppf)Cl₂ (82 mg, 0.1 mmol)at 25° C. under nitrogen. Then the mixture was heated to reflux, stirredfor 3 h and filtered. The filtrate was concentrated to offer the crudeproduct. Water (10 mL) was added, and the mixture was extracted withethyl acetate (100 mL). Then 2 N HCl was added to the aqueous layer,adjusted to pH=6-7, then extracted with THF in ethyl acetate (20% v/v,35 mL×3). The organic layers were dried over anhydrous sodium sulfate,filtered, and evaporated to obtain Compound 178D.

A mixture of Compound 178D (88 mg, 0.33 mmol), Intermediate G (105 mg,0.34 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) indichloromethane (2 mL) and DMF (2 mL) was stirred at 25° C. for 5 h.Then it was treated with water (20 mL), extracted with dichloromethane(20 mL×3), dried over anhydrous sodium sulfate, concentrated in vacuumand purified with prep-HPLC to obtain Compound 178. LC-MS (m/z): 560[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) δ (ppm) 0.63-0.69 (m, 4H), 2.13 (br,2H), 3.03-3.05 (br, 2H), 3.36-3.61 (m, 5H), 4.51 (d, J=8.0 Hz, 1H), 4.95(d, J=3.2 Hz, 1H), 7.08 (s, 2H), 7.34 (s, 1H), 7.41-7.44 (m, 2H),7.58-7.62 (m, 1H), 7.83-7.95 (m, 3H), 8.54 (d, J=3.2 Hz, 1H).

Example 179

A mixture of Compound 178D (88 mg, 0.33 mmol), Intermediate A (100 mg,0.35 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) indichloromethane (15 mL) and DMF (2 mL) was stirred at 25° C. for 15 h.Then it was treated with water (20 mL), extracted with dichloromethane(20 mL×3), dried over anhydrous sodium sulfate, concentrated in vacuumand purified with prep-HPLC to obtain Compound 179. LC-MS (m/z): 528[M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) δ (ppm) 2.09-2.14 (m, 4H), 2.81-2.84 (m,2H), 3.41-3.45 (m, 2H), 3.72-3.88 (m, 2H), 4.15 (s, 4H), 4.41 (m, 1H),5.06 (d, J=2.0 Hz, 1H), 6.73-6.80 (m, 3H), 7.43-7.52 (m, 3H), 7.72-7.76(m, 2H), 7.92 (d, J=8.4 Hz, 2H), 8.56 (d, J=2.8 Hz, 1H), 11.79 (brs,1H).

Example 180

To a solution of Compound 174D (290 mg, 1.07 mmol) in DCM (5 mL) wasadded DAST (1 mL, excess) at room temperature and the resultant mixturewas stirred at 30° C. overnight. Poured into ice-water (100 mL) andextracted with DCM (50 mL×3). The combined organic phase was washed withwater (5 mL) and brine (5 mL), and dried over anhydrous sodium sulfate.The crude product was purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, 10% v/v) to obtainCompound 180A.

To a solution of Compound 180A (130 mg, 0.43 mmol) in THF/water (6 mL,4:1, v/v) was added LiOH.H₂O (73 mg, 1.73 mmol). The mixture was stirredat 25° C. for 2 h. After the reaction, it was adjusted to pH 3 with HC(1 N) and separated. The organic phase was dried over sodium sulfate.Filtered and concentrated to furnish the Compound 180C.

To a mixture of Compound 180C (98 mg, 0.36 mmol) in DMF (10 mL) wasadded EDCI.HCl (104 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and Compound(A) (100 mg, 0.36 mmol) under nitrogen. The mixture was stirred at 25°C. overnight. TLC and LC-MS showed the starting material was consumedcompletely. Then sat. sodium bicarbonate (5 mL) was added to the mixturewhich was extracted with EA (50 mL×3). The combined organic layers werewashed with water (5 mL×3) and brine (5 mL), dried over anhydrous sodiumsulfate, and concentrated to offer the crude product. The crude productwas purified with prep-HPLC to offer Compound 180. LC-MS (m/z): 533[M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) major characteristic peaks: δ (ppm)1.96-2.00 (m, 2H), 2.11-2.14 (m, 2H), 3.11-3.20 (m, 2H), 3.46-3.50 (m,1H), 3.56-3.62 (m, 2H), 3.71-3.77 (m, 1H), 4.01 (s, 4H), 4.50-4.53 (m,1H), 4.79 (d, J=3.2 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 6.70 (dd, J=2.0,8.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 7.04 (d, J=3.6 Hz, 1H), 7.15 (t,J=8.4 Hz, 2H), 7.23 (d, J=4.0 Hz, 1H), 7.63-7.67 (m, 2H).

Example 181

To a solution of 174 (50 mg, 0.08 mmol) in MeOH (10 mL) was addedhydroxylamine hydrochloride (112 mg, 1.6 mmol). The mixture was stirredovernight at 25° C. LC-MS showed the starting material was consumedcompletely, and the solvent was evaporated. The crude product waspurified with prep-HPLC to offer Compound 181. LC-MS (m/z): 526 [M+1]⁺;¹H-NMR (CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 1.97-2.00(m, 2H), 2.13-2.15 (m, 2H), 3.14-3.23 (m, 2H), 3.42-3.46 (m, 1H),3.57-3.63 (m, 2H), 3.74-3.81 (m, 1H), 4.15-4.20 (m, 4H), 4.57-4.69 (m,1H), 4.70 (d, J=2.8 Hz, 1H), 6.74-6.86 (m, 2H), 6.90-6.94 (m, 1H),7.10-7.15 (m, 2H), 7.27 (d, J=4.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H),7.61-7.69 (m, 2H).

Example 182

A mixture of Compound 178C (1.3 g, 4 mmol), 2-bromopyridine (628 mg, 4mmol), Pd(dppf)₂Cl₂ (160 mg, 0.2 mmol), and Na₂CO₃ (1.27 g, 12 mmol) indioxane (30 mL) and water (4 mL) was stirred under nitrogen at 100° C.for 3 h. The reaction mixture was cooled to room temperature and dilutedwith ethyl acetate (50 mL). The mixture was filtered and the filtratewas treated with water (50 mL), extracted with ethyl acetate (50 mL×2),then the water layer was adjusted to pH 3 by aqueous HCl solution (3 N),and extracted with ethyl acetate (50 mL×2). The ethyl acetate layer waswashed with water (50 mL×2), dried over sodium sulfate, filtered, andconcentrated to furnish the Compound 182A.

A mixture of Compound 182A (90 mg, 0.36 mmol), EDCI.HCl (103 mg, 0.54mmol), HOBT (73 mg, 0.54 mmol), and Intermediate G (111 mg, 0.36 mmol)in DCM (5 mL) was stirred at 10° C. for 18 h. Then the mixture wasdiluted by ethyl acetate (50 mL), washed with sat. sodium bicarbonatesolution (50 mL×2) and brine (50 mL), and dried over anhydrous sodiumsulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 182. LC-MS (m/z): 542 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 0.48-0.59 (m, 4H),2.03-2.24 (m, 4H), 3.17-3.26 (m, 2H), 3.54-3.81 (m, 5H), 4.62 (d, J=9.2Hz, 1H), 4.94-4.96 (m, 1H), 7.00-7.03 (m, 1H), 7.09-7.11 (m, 1H),7.34-7.36 (m, 1H), 7.47-7.59 (m, 3H), 8.02-8.14 (m, 4H), 8.71-8.74 (m,1H).

Example 183

A mixture of Compound 178D (88 mg, 0.33 mmol), Intermediate C (105 mg,0.34 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) indichloromethane (15 mL) was stirred at 25° C. for 15 h. Then it wastreated with water (20 mL), extracted with dichloromethane (20 mL×3),dried over anhydrous sodium sulfate, concentrated in vacuum and purifiedwith prep-HPLC to obtain Compound 183. LC-MS (m/z): 546 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) & (ppm) 2.02-2.19 (m, 4H), 3.15-3.31 (m, 2H), 3.52-3.56(m, 3H), 3.79-3.80 (m, 1H), 4.04-4.08 (m, 4H), 4.56 (d, J=10.4 Hz, 1H),4.81 (d, J=2.8 Hz, 1H), 6.57-6.68 (m, 2H), 7.48 (d, J=8.4 Hz, 2H),7.71-7.76 (m, 1H), 8.01-8.07 (m, 3H), 8.59 (d, J=3.2 Hz, 1H).

Example 184

To a solution of Compound 178 (56 mg, 0.086 mmol) in MeOH (20 mL) wasadded hydroxylamine hydrochloride (120 mg, 1.72 mmol) at 25° C., thenthe reaction was stirred at 55° C. for 14 h. Then it was purified withprep-HPLC to obtain Compound 184. LC-MS (m/z): 553 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 0.77-0.85 (m, 4H),2.03-2.06 (m, 2H), 2.20-2.22 (m, 2H), 3.19-3.26 (m, 1H), 3.62-3.92 (m,5H), 4.60-4.89 (m, 2H), 5.02 (d, J=2.8 Hz, 1H), 7.16-7.51 (m, 5H),7.51-7.74 (m, 1H), 7.86-7.98 (m, 3H), 8.51-8.54 (m, 1H).

Example 185

A mixture of Compound 185A (22.2 g, 200 mmol), 1,2-dibromoethane (55.8g, 300 mmol), and K₂CO₃ (55.2 g, 600 mmol) in DMSO (270 mL) was stirredat 100° C. for 10 h under nitrogen protection. Then it was cooled toroom temperature and extracted with ethyl acetate (100 mL×3). The ethylacetate layers were combined and washed with water (50 mL×3) and brine(50 mL), dried over sodium sulfate, and concentrated to offer the titleCompound 185B.

A mixture of Compound 185B (1.37 g, 10 mmol) and Br₂ (1.6 g, 10 mmol) inDCM (27 mL) was stirred at 25° C. for 24 h, cooled to room temperature,quenched by NH₄Cl (20 mL), and extracted with DCM (100 mL×3). The DCMlayers were combined and washed with water (50 mL×3) and brine (50 mL),dried over sodium sulfate, concentrated and recrystallized from methanolto offer the title Compound 185C.

To a mixture of Compound 185C (3.23 g, 15 mmol) in THF (27 mL) at −65°C. was added by n-BuLi solution (6.45 mL), and the mixture was stirredat −65° C. for 1 h. Then a solution of Compound A4 (1.98 g, 5 mmol) inTHF (10 mL) was added. The resultant mixture was stirred for 1 h,quenched by NH₄Cl (20 mL), and extracted with EA (100 mL×3). The EAlayers were combined and washed with water (50 mL×3) and brine (50 mL),dried over sodium sulfate, concentrated, and purified with flash columnchromatography on silica gel with EA in PE (1/20 to 1/5 v/v) to offerthe title Compound 185D.

To a mixture of Compound 185D (1.4 g, 3 mmol) in THF (17 mL) at −90° C.was added L-Selectride (1 Min THF, 6 mL), then it was stirred at −90° C.for 0.5 h, quenched by NH₄Cl (20 mL), and extracted with EA (100 mL×3).The EA layers were combined and washed with water (50 mL×3) and brine(50 mL), dried over sodium sulfate, concentrated, and purified withflash column chromatography on silica gel with EA in PE (1/2 v/v) tooffer the title Compound 185E.

A mixture of Compound 185E (1.4 g, 3 mmol) and TBAF.3H₂O (945 mg, 3mmol) in THF (17 mL) at 20° C. was stirred for 15 h. Then it was dilutedby EA (50 mL), washed with water (10 mL×3) and brine (10 mL), dried oversodium sulfate, concentrated, and purified with flash columnchromatography on silica gel with methanol in DCM (1/100 to 1/20 v/v) tooffer the title Compound 185F.

To a mixture of Compound 185F (800 mg, 2.2 mmol) and TEA (404 mg, 4.4mmol) in DCM (8 mL) at 20° C. was added MsCl (1.77 mL, 2.2 mmol). Themixture was stirred for 30 min, quenched by water (5 mL), and extractedwith DCM (10 mL×3). The combined DCM layers were washed with water (10mL×3) and brine (10 mL), dried over sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel with methanol inDCM (1/100 to 1/50 v/v) to offer the title Compound 185G.

A mixture of Compound 185G (390 mg, 0.9 mmol) and pyrrolidine (632 mg, 9mmol) in THF (8 mL) at 50° C. was stirred for 13 h then concentrated.The residue was dissolved into EA (50 mL), washed with water (10 mL×3)and brine (10 mL), dried over sodium sulfate, and concentrated to offerthe title Compound 185H.

A mixture of Compound 185H (380 mg, 0.9 mmol) and LiOH.H₂O (77 mg, 1.8mmol) in EtOH (4 mL) was stirred at 100° C. for 13 h then concentrated.The residue was dissolved into DCM (50 mL), washed with water (10 mL×3)and brine (10 mL), dried over sodium sulfate, and concentrated to offerthe title Compound 1851.

A mixture of Compound 1851 (180 mg, 0.644 mmol), Compound 11E (159 mg,0.644 mmol), HATU (294 mg, 0.773 mmol) and DIPEA (125 mg, 0.966 mmol) inDCM (4 mL) was stirred at r.t. overnight then concentrated. The residuewas dissolved into DCM (50 mL), washed with water (10 mL×3) and brine(10 mL), dried over sodium sulfate, concentrated, and purified withchiral HPLC to offer Compound 185. LC-MS (m/z): 508 [M+1]⁺; ¹H-NMR(CDCl₃, 400 MHz) major characteristic peaks: δ (ppm) 1.75 (m, 4H),2.61-2.69 (m, 4H), 2.77-2.81 (m, 1H), 2.92-2.97 (m, 1H), 4.03-4.10 (m,1H), 4.18-4.36 (m, 4H), 5.19 (d, J=7.6 Hz, 1H), 5.27-5.29 (m, 1H), 6.91(s, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.27-7.30 (m, 1H), 7.37-7.39 (m, 1H),7.40-7.42 (m, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H).

Example 186

A mixture of Compound 182A (90 mg, 0.36 mmol), EDCI.HCl (103 mg, 0.54mmol), HOBT (73 mg, 0.54 mmol), and Intermediate A (100 mg, 0.36 mmol)in DCM (5 mL) was stirred for 18 h at 10° C. Then the mixture wasdiluted by ethyl acetate (50 mL), washed with sat. sodium bicarbonatesolution (50 mL×2) and brine (50 mL), and dried over anhydrous sodiumsulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 186. LC-MS (m/z): 510 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 2.02-2.04 (m, 4H),3.13-3.20 (m, 2H), 3.49-3.67 (m, 4H), 4.06-4.09 (m, 4H), 4.55-4.57 (m,1H), 4.81 (d, J=3.2 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 6.73 (dd, J=8.4,2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.75 (t,J=6.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 2H), 8.18 (d, J=8.4 Hz, 1H), 8.30-8.32(m, 1H), 8.80 (d, J=5.2 Hz, 1H).

Example 187

A mixture of Compound 182A (90 mg, 0.36 mmol), EDCI.HCl (103 mg, 0.54mmol), HOBT (73 mg, 0.54 mmol), and Intermediate C (107 mg, 0.36 mmol)in DCM (5 mL) was stirred for 18 h at 10° C. Then the mixture wasdiluted by ethyl acetate (50 mL), washed with sat. sodium bicarbonatesolution (50 mL×2) and brine (50 mL), and dried over anhydrous sodiumsulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 187. LC-MS (m/z): 528 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 2.04-2.16 (m, 4H),3.31-3.32 (m, 2H), 3.52-3.19 (m, 4H), 4.05-4.11 (m, 4H), 4.56-4.59 (m,1H), 4.81 (d, J=3.2 Hz, 1H), 6.58 (s, 1H), 6.64 (dd, J=11.2, 2.0 Hz,1H), 7.59 (d, J=8.4 Hz, 2H), 7.64-7.67 (m, 1H), 8.04 (d, J=8.0 Hz, 2H),8.14 (d, J=8.0 Hz, 1H), 8.20-8.23 (m, 1H), 8.76 (d, J=9.0 Hz, 1H).

Example 188

To a solution of Compound 151A) (85 mg, 0.37 mmol) and Intermediate H(104 mg, 0.37 mmol) in dichloromethane (6 mL) and DMF (2 mL) was addedHATU (208 mg, 0.55 mmol) at 25° C. Then the reaction was stirred at 28°C. for 15 hours. Then the reaction mixture was treated with water (40mL), extracted with DCM (20 mL×2), washed with brine (10 mL), dried oversodium sulfate, and concentrated. The crude product was purified withprep-HPLC to obtain Compound 188. LC-MS (m/z): 499 [M+1]⁺; ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm) 2.08-2.40 (m, 2H), 2.70-3.35 (m, 2H),3.50-4.10 (m, 3H), 4.24-4.29 (m, 6H), 4.78 (s, 1H), 6.76-6.85 (m, 2H),7.67-7.70 (m, 1H), 7.87 (d, J=1.6 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 8.10(d, J=8.8 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.48 (s, 1H), 8.76 (br, 1H).

Example 189

A mixture of Compound 175E (100 mg, 0.408 mmol) and Intermediate A (114mg, 0.408 mmol) and HATU (155 mg, 0.612 mmol) in dichloromethane (4 mL)and DMF (2 mL) was stirred at 25° C. for 15 h. Then it was treated withwater (20 mL), extracted with dichloromethane (20 mL×3), dried overanhydrous sodium sulfate, concentrated in vacuum and purified withprep-HPLC to obtain Compound 189. LC-MS (m/z): 506 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) δ (ppm) 2.03-2.24 (m, 6H), 3.12-3.25 (m, 3H), 3.60-3.71(m, 2H), 3.82-3.95 (m, 1H), 4.19-4.28 (m, 2H), 4.55-4.58 (m, 1H), 4.93(d, J=2.8 Hz, 1H), 6.85-6.92 (m, 3H), 7.61-7.90 (m, 2H), 8.00 (s, 4H),8.59 (d, J=2.8 Hz, 1H).

Example 190

To a solution of 189 (40 mg, 0.065 mmol) in MeOH (18 mL) was addedhydroxylamine hydrochloride (90 mg, 1.29 mmol) at 25° C., then thereaction was stirred at 55° C. for 14 h. Then it was purified withprep-HPLC to obtain Compound 190. LC-MS (m/z): 521 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 1.91-2.10 (m, 4H),2.56-3.17 (m, 1H), 3.17-3.77 (m, 4H), 4.12-4.19 (m, 4H), 4.46-4.71 (m,2H), 4.83-4.84 (m, 1H), 6.70-6.90 (m, 3H), 7.19-7.34 (m, 2H), 7.57-7.63(m, 1H), 7.82-7.85 (m, 3H), 8.47-8.50 (m, 1H).

Example 191

To a solution of 188 (30 mg, 0.049 mmol) in MeOH (15 mL) was addedhydroxylamine hydrochloride (80 mg, 0.98 mmol) at 30° C., then thereaction was stirred at 55° C. for 4 h. Then it was purified withprep-HPLC to obtain Compound 191. LC-MS (m/z): 514 [M+1]⁺; ¹H-NMR(CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 2.40-2.71 (m, 2H),3.55-3.64 (m, 2H), 4.02-4.50 (m, 9H), 4.63-4.83 (m, 1H), 6.78-6.85 (m,2H), 7.47-7.51 (m, 2H), 7.68-7.90 (m, 4H).

Example 192

To a solution of Intermediate V (100 mg, 0.29 mmol) and Compound 63D (72mg, 0.29 mmol) in DMF (10 mL) was added EDCI.HCl (84 mg, 0.44 mmol), andHOBt (59 mg, 0.44 mmol) under nitrogen. The mixture was stirred at 25°C. overnight. TLC and LC-MS showed the starting material was consumedcompletely, sat. sodium bicarbonate (5 mL) was added to the mixture andthen extracted with EA (50 mL×3). The combined organic layers werewashed with water (5 mL×3) and brine (5 mL), dried over anhydrous sodiumsulfate, and concentrated to offer the crude product. The crude productwas purified with prep-HPLC to offer Compound 192. LC-MS (m/z): 571[M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) major characteristic peaks: δ (ppm)1.31-1.34 (m, 6H), 2.00-2.03 (m, 3H), 2.14-2.17 (m, 2H), 2.55-2.61 (m,2H), 2.64-2.72 (m, 1H), 2.78-2.98 (m, 2H), 3.15-3.25 (m, 2H), 3.51-3.55(m, 1H), 3.60-3.66 (m, 2H), 3.74-3.79 (m, 3H), 4.62-4.65 (m, 1H), 4.92(d, J=2.8 Hz, 1H), 7.02 (dd, J=1.2, 8.8 Hz, 1H), 7.08-7.15 (m, 3H), 7.29(dd, J=1.6, 8.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H).

Example 193

A mixture of Compound 193A (13 g, 62 mmol), methyl acrylate (16.0 g, 187mmol), Pd(PPh₃)₂Cl₂ (2.0 g, 3.0 mmol), and K₂CO₃ (22 g, 156 mmol) in DMF(100 mL) was stirred at 100° C. for 12 h, then cooled to roomtemperature and filtered. The filtrate was treated with water (50 mL),extracted with DCM (100 mL×2), washed with water (100 mL×3) and brine(100 mL), dried over sodium sulfate, concentrated, and purified withflash column chromatography on silica gel (20% ethyl acetate inpetroleum) to furnish Compound 193B.

To a solution of Compound 193B (11.5 g, 54 mmol) in MeOH (100 mL) wasadded Pd/C (1.1 g), then the mixture was stirred at room temperature for12 h under H₂, then filtered. The filtrate was concentrated to furnishthe crude Compound 193C.

To a solution of AlLiH₄ (1.56 g, 41 mmol) in THF (100 mL) was addedCompound 193C (9.0 g, 41 mmol) in THF (20 mL) dropwise at −78° C. undernitrogen, then the mixture was stirred at −78° C. for 2 h and quenchedwith Na₂SO₄.10H₂O. Silica gel was added and the resultant mixture wasfiltered. The filtrate was concentrated to furnish the crude Compound193D.

To a solution of Compound 193D (8 g, 42 mmol) in THF (80 mL) was addedK₂CO₃ (5.8 g, 42 mmol), water (25 mL), and CbzCl (7.1 mL) underice-cooling, and the resulting mixture was stirred at 25° C. for 12 h.EA (200 mL) was added. The organic layer was separated, dried oversodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (20% ethyl acetate in petroleum) to furnishCompound 193E.

To a solution of Compound 193E (12.2 g, 37.5 mmol) in DCM (100 mL) wasadded DMP (16.0 g, 37.5 mmol) at 0° C., then the mixture was stirred atroom temperature for 2 h, then filtered. The filtrate was concentratedand the resulting residue was purified with flash column chromatographyon silica gel (20% ethyl acetate in petroleum) to furnish Compound 193F.

Compound 193F (9.8 g, 30 mmol) was added to a solution of Na₂S₂O₅ (5.8g, 30 mmol) in water (150 mL), then the mixture was stirred for 2 h atroom temperature. And after the addition of NaCN (3 g, 61 mmol) themixture was stirred for 15 h, diluted with EA (50 mL), extracted with EA(100 mL×2), washed with sat. sodium bicarbonate (100 mL×2) and brine(100 mL), dried over sodium sulfate, concentrated, and purified withflash column chromatography on silica gel (20% ethyl acetate inpetroleum) to furnish Compound 193G.

To a solution of Compound 193G (10 g, 28 mmol) in EtOH (150 mL) cooledto 0° C. was bubbled a gentle stream of HCl gas (dried over con. H₂SO₄)for 5 h. Then the mixture was treated with water slowly at 0° C.,stirred at room temperature for 2 h, then extracted with DCM (100 mL×2),washed with brine (100 mL), dried over sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (20% ethylacetate in petroleum) to furnish Compound 193H.

To a solution of Compound 193H (845 mg, 2.13 mmol) in DCM (20 mL) wasadded DMP (1.1 g, 2.55 mmol) at 0° C., then the mixture was stirred atroom temperature for 2 h, then filtered. The filtrate was concentratedand the resulting residue was purified with flash column chromatographyon silica gel (20% ethyl acetate in petroleum) to furnish Compound 1931.

To a solution of Compound 1931 (730 mg, 1.84 mmol) in DCM (20 mL) wasadded DAST (1.5 g, 9.24 mmol), then the mixture was stirred at roomtemperature for 12 h, poured into ice water, extracted with DCM (50mL×2), washed with brine (50 mL), dried over sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (20% ethyl acetate in petroleum) to furnish Compound 193J.

Compound 193J (730 mg, 1.75 mmol) was dissolved in ethanol (20 mL), thenPd(OH)₂ (100 mg) was added, then the mixture was stirred at roomtemperature under H₂ overnight, then filtered and evaporated to furnishthe product Compound 193K.

To a solution of Compound 193K (350 mg, 1.24 mmol) in CH₃CN (5 mL) wasadded CH₃I (526 mg, 3.71 mmol), then the mixture was stirred at 70° C.for 2 h, then cooled to room temperature, evaporated and purified withflash column chromatography on silica gel (20% ethyl acetate inpetroleum) to furnish Compound 193L.

To a solution of Compound 193L (200 mg, 0.67 mmol) in THF (10 mL) wasadded LiOH (85 mg, 2.02 mmol) in water (2 mL), then the mixture wasstirred at room temperature for 2 h, then evaporated to remove solvent.The mixture was treated with water (50 mL), adjusted to pH 2 withdiluted HCl, then extracted with EA (50 mL×2), washed with brine (50mL), dried over sodium sulfate, and concentrated to furnish the Compound193M.

A mixture of Compound 193M (96 mg, 0.36 mmol), Intermediate G (111 mg,0.36 mmol), EDCI.HCl (103 mg, 0.54 mmol), and HOBt (73 mg, 0.54 mmol) inDCM (10 mL) was stirred at room temperature overnight. The mixture wastreated with water (50 mL), extracted with DCM (50 mL×2), washed withwater (50 mL×2) and brine (50 mL), dried over sodium sulfate,concentrated, and purified with prep-HPLC to offer Compound 193. LC-MS(m/z): 562 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 0.66-0.75 (m, 4H), 2.13 (s, 8H), 2.24-2.31 (m, 1H), 2.41-2.49 (m,1H), 2.87-2.90 (m, 4H), 3.13 (s, 3H), 3.39-3.64 (m, 5H), 3.76 (s, 2H),4.50 (s, 1H), 5.05 (s, 1H), 6.90 (s, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.19(s, 2H), 7.27 (s, 1H), 7.29 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 11.62 (s,1H).

Example 194

To a solution of Intermediate V (100 mg, 0.29 mmol) in DMF (10 mL) wasadded HATU (167 mg, 0.44 mmol). After stirring for two hours at 25° C.,Compound 133D (71 mg, 0.29 mmol) was added and the resultant mixture wasstirred overnight at 25° C. TLC and LC-MS showed the starting materialwas consumed completely, and sat. sodium bicarbonate (5 mL) was added tothe mixture which was extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with water (5 mL×3) and brine (5mL), dried over anhydrous sodium sulfate, and concentrated to offer thecrude product. The crude product was purified with prep-HPLC to offerCompound 194. LC-MS (m/z): 569 [M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) majorcharacteristic peaks: δ (ppm) 1.27-1.31 (m, 6H), 2.02-2.07 (m, 2H),2.20-2.23 (m, 2H), 3.19-3.24 (m, 1H), 3.46-3.56 (m, 1H), 3.60-3.83 (m,5H), 4.56-4.57 (m, 1H), 4.69-4.72 (m, 1H), 4.98 (d, J=2.4 Hz, 1H), 7.06(d, J=8.4 Hz, 1H), 7.22 (t, J=8.4 Hz, 2H), 7.35 (dd, J=2.0, 8.4 Hz, 1H),7.50 (d, J=2.0 Hz, 1H), 7.64-7.67 (m, 3H), 7.71-7.74 (m, 3H).

Example 195

A mixture of Compound 175B (608 mg, 2 mmol), 2-bromopyridine (314 mg, 2mmol), Pd(dppf)Cl₂ (82 mg, 0.1 mmol), and Na₂CO₃ (636 mg, 6 mmol) indioxane (15 mL) and water (2 mL) was stirred at 100° C. for 3 h andconcentrated. The mixture was treated with water (50 mL) and extractedwith DCM (50 mL×3). The aqueous layer was acidified with 1 M HCl andextracted with DCM (50 mL×3). The aqueous layer was purified withprep-HPLC to offer Compound 195A.

A solution of Compound 195A (100 mg, 0.44 mmol), Intermediate A (122 mg,0.44 mmol), and HATU (335 mg, 0.88 mmol) in DMF (10 mL) was stirred at25° C. for 16 h. Then it was treated with EA (50 mL), washed with water(20 mL×3) and brine (20 mL×1), dried over anhydrous sodium sulfate,concentrated, and purified with prep-HPLC to obtain Compound 195. LC-MS(m/z): 488 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.75 (s, 4H), 2.64 (m, 4H), 2.81-2.94 (m, 2H), 4.15 (s, 4H), 4.27(s, 1H), 4.99 (s, 1H), 6.77 (m, 3H), 7.31 (m, 1H), 7.72 (s, 2H), 8.00(m, 2H), 8.26 (m, 2H), 8.66 (m, 1H).

Example 196

A mixture of Compound 196A (10 g, 106 mmol) and ethyl3-bromo-2-oxopropanoate (22.8 g, 117 mmol) in THF (300 mL) was stirredat r.t. for 1 h, then heated to 80° C. overnight, cooled to roomtemperature, diluted with water (50 mL), adjusted to pH >9 with Na₂CO₃,and extracted with ethyl acetate (100 mL×3). The ethyl acetate layerswere combined and washed with brine (100 mL), dried over sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 33% v/v) to offer Compound 196B.

To a suspension of AlLiH₄ (4.2 g, 111.3 mmol) in THF (200 mL) was addedCompound 196B (10.7 g, 55.6 mmol) in THF (50 mL) dropwise at 0° C. undernitrogen. Then the mixture was stirred at 0° C. for 30 min, quenchedwith Na₂SO₄.10H₂O and filtered. The filtrate was concentrated to furnishthe crude Compound 196C.

To a solution of Compound 196C (6.9 g, 46.6 mmol) in DCM (140 mL) wasadded DMP (23.7 g, 55.9 mmol) at 0° C., then the mixture was stirred atroom temperature for 2 h, then filtered. The filtrate was concentratedand the resulting residue was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, 33% v/v) to furnishCompound 196D.

Compound 196D (2.5 g, 17.1 mmol) was added to a solution of Na₂S₂O₅(3.25 g, 17.1 mol) in water (300 mL), then the mixture was stirred for 2h at room temperature. And after the addition of NaCN (1.68 g, 34.2mol), it was stirred again for 15 h, diluted with water (50 mL), stirredfor 30 min, and filtered. The solid was collected, washed with water (50mL), and dried to offer Compound 196E.

To a solution of Compound 196E (2.8 g, 16.2 mmol) in EtOH (80 mL) at 0°C. was bubbled a gentle stream of HCl gas (dried over con. H₂SO₄) for 5h. Then the mixture was treated with ice-water slowly at 0° C., stirredat room temperature for 2 h, adjusted to pH >7 with sodium bicarbonate,extracted with DCM (100 mL×2), washed with brine (100 mL), dried oversodium sulfate, and concentrated to furnish Compound 196F.

To a solution of Compound 196F (1.7 g, 7.72 mmol) in DCM (30 mL) wasadded DMP (3.93 g, 9.26 mmol), then the mixture was stirred at 0° C. for2 h, then filtered. The filtrate was concentrated and the resultingresidue was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, 50% v/v) to furnish Compound 196G.

To a solution of Compound 196G (1.68 g, 7.72 mmol) in DCM (60 mL) wasadded DAST (6.22 g, 38.6 mmol), then the mixture was stirred at roomtemperature overnight, poured into ice water, extracted with DCM (100mL×2), washed with brine (50 mL), dried over sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 33% v/v) to furnish Compound196H.

To a solution of Compound 196H (960 mg, 4.0 mmol) in THF (20 mL) andwater (2 mL) was added LiOH (252 mg, 6.0 mmol), then the mixture wasstirred at room temperature overnight, then evaporated to removesolvent. The mixture was treated with water (50 mL), adjusted to pH 2with diluted HCl, and purified with prep-HPLC to furnish the Compound1961.

A mixture of Compound 1961 (100 mg, 0.471 mmol), Intermediate C (140 mg,0.471 mmol), and HATU (215 mg, 0.565 mmol) in DCM (2 mL) was stirred atroom temperature overnight and concentrated. The residue was dissolvedinto DCM (50 mL), washed with water (50 mL) and brine (10 mL), driedover sodium sulfate, concentrated, and purified with chiral HPLC tooffer Compound 196. LC-MS (m/z): 490 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz)major characteristic peaks: δ (ppm) 1.82-2.01 (m, 4H), 3.05-3.11 (m,2H), 3.31-3.38 (m, 1H), 3.44-3.52 (m, 3H), 4.19-4.23 (m, 4H), 4.35-4.41(m, 1H), 4.66-4.67 (m, 1H), 6.62 (s, 1H), 6.69-6.73 (m, 1H), 7.03-7.07(m, 1H), 7.39-7.43 (m, 1H), 7.59-7.61 (m, 1H), 8.26 (s, 1H), 8.59 (d,J=6.8 Hz, 1H), 8.68-8.70 (m, 1H), 9.41 (brs, 1H).

Example 197

An aqueous solution of KOH (4.9 g, 87.5 mmol) in water (10 mL) was addedto a stirred solution of 4-fluorophenol 197A (8.4 g, 75 mmol) inmethanol (25 mL). When the addition was complete, the mixture wasevaporated in vacuum and the residual solid was dissolved in1-methyl-2-pyrrolidinone (30 mL) and 3-fluorobromobenzene (13 g, 75mmol) was added and the mixture was refluxed for 24 hours, then cooledto room temperature, poured into water (150 mL) and extracted with ether(30 mL×2). The combined extracts were dried over sodium sulfate andconcentrated. The residue was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, from 10% to 50% v/v) tofurnish Compound 197B.

To a solution of Compound 197B (2.66 g, 10 mmol) in THF (30 mL) wasadded dropwise n-BuLi solution (2.5 M, 4 mL, 10 mmol) at −78° C. undernitrogen. The mixture was stirred at −78° C. for 0.5 h, and then themixture was added to a solution of diethyl oxalate (3 g, 20 mmol) in THF(20 mL) at −78° C. The mixture was stirred at room temperatureovernight. The mixture was quenched with saturated aqueous NH₄Clsolution (40 mL). The reaction mixture was extracted with EA (50 mL×3),dried over anhydrous sodium sulfate, and concentrated. The residue waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 10% to 50% v/v) to furnish Compound 197C.

Lithium hydroxide (420 mg, 10 mmol) was added to a solution of Compound197C (1.44 mg, 5 mmol) in EtOH (20 mL) and water (5 mL). The reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas added 1 N HCl to adjust to pH 7 and concentrated in vacuum. Theresidue was extracted with EA (50 mL×3), dried over anhydrous sodiumsulfate, and concentrated to furnish Compound 197D.

A mixture of Compound 197D (262 mg, 1 mmol), Intermediate A (278 mg, 1mmol), and HATU (760 mg, 2 mmol) in DMF (20 mL) was stirred at 25° C.for 16 h. Then it was diluted with DCM (70 mL), washed with water (50mL×3) and brine (50×2 mL), dried over anhydrous sodium sulfate,concentrated, and purified with prep-HPLC to obtain Compound 197. LC-MS(m/z): 521 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ(ppm) 1.79-1.81 (m, 4H), 2.70-2.75 (m, 4H), 2.83-3.02 (m, 2H), 4.22 (s,4H), 4.23-4.27 (m, 1H), 5.04 (s, 1H), 6.81-6.86 (m, 3H), 6.87-6.98 (m,4H), 6.98-7.05 (m, 1H), 7.27 (m, 1H), 7.35-7.42 (t, J=4.8 Hz, 1H), 7.77(s, 1H), 7.95-7.97 (d, J=4.2 Hz, 1H).

Example 198

A mixture of Compound 193M (80 mg, 0.3 mmol), Intermediate A (83 mg, 0.3mmol), EDCI.HCl (86 mg, 0.45 mmol), and HOBt (61 mg, 0.45 mmol) in DCM(10 mL) was stirred at 25° C. overnight. Then the reaction mixture wasconcentrated to remove DCM. The residue was purified with prep-HPLC tooffer Compound 198. LC-MS (m/z): 530 [M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz)major characteristic peaks: δ (ppm) 2.13 (s, 8H), 2.30-2.37 (m, 1H),2.45-2.53 (m, 1H), 2.85-2.88 (m, 3H), 2.91 (s, 1H), 3.10 (s, 3H),3.43-3.46 (m, 2H), 3.79 (s, 2H), 4.00-4.09 (m, 5H), 4.26 (s, 1H),4.45-4.48 (m, 1H), 5.01 (s, 1H), 6.80 (s, 2H), 6.86-6.90 (m, 1H),6.98-7.01 (m, 1H), 7.21-7.24 (m, 1H), 7.61 (t, J=8.0 Hz, 1H), 11.89 (s,1H).

Example 199

A mixture of Compound 1961 (100 mg, 0.471 mmol), Intermediate G (146 mg,0.471 mmol), and HATU (215 mg, 0.565 mmol) in DCM (2 mL) was stirred atroom temperature overnight and concentrated. The residue was dissolvedinto DCM (50 mL), washed with water (50 mL) and brine (10 mL), driedover sodium sulfate, concentrated, and purified with chiral HPLC tooffer Compound 199. LC-MS (m/z): 505 [M+1]⁺; ¹H-NMR (DMSO-d₆, 400 MHz)major characteristic peaks: δ (ppm) 0.61-0.65 (m, 2H), 0.77-0.82 (m,2H), 1.82-2.00 (m, 4H), 3.06-3.14 (m, 2H), 3.35-3.42 (m, 1H), 3.49-3.53(m, 3H), 3.79-3.84 (m, 1H), 4.38-4.45 (m, 1H), 4.75-4.76 (m, 1H),7.04-7.08 (m, 1H), 7.15-7.21 (m, 2H), 7.30 (d, J=1.6 Hz, 1H), 7.39-7.44(m, 1H), 7.62-7.64 (m, 1H), 8.23 (s, 1H), 8.59 (d, J=7.2 Hz, 1H),8.69-8.71 (m, 1H), 9.52 (brs, 1H).

Example 200

Compound 200A (1.72 g, 10.0 mmol), 1,5-dibromopentane (2.52 g, 11.0mmol), and K₂CO₃ (1.51 g, 11.0 mmol) were taken in water (5 mL) andheated at 100° C. for 20 min. in a microwave oven. The reaction mixturewas cooled to room temperature and extracted with ethyl acetate (30mL×2). The combined organic extracts were dried over sodium sulfate,evaporated, and purified with flash column chromatography on silica gel(petroleum ether in ethyl acetate, 10% v/v) to offer Compound 200B.

To a solution of Compound 200B (240 mg, 1.0 mmol) in THF (25 mL) wasadded dropwise n-BuLi (2.5 Min hexane, 0.48 mL) at −60° C. undernitrogen atmosphere. The reaction mixture was stirred for 30 min. at thesame temperature. The resulting mixture was added to the solution ofdiethyl oxalate (292 mg, 2.0 mmol) in THF (25 mL) at −60° C. Thereaction mixture was stirred for 2 hours at −60° C., quenched with satNH₄Cl, and extracted with ethyl acetate (50 mL×2). The combined organicphases were washed with brine (50 mL), dried over sodium sulfate,evaporated, and purified with prep-TLC (petroleum ether in ethylacetate, 20% v/v) to yield Compound 200C.

To a solution of Compound 200C (97 mg, 0.37 mmol) in MeOH (5 mL) wasadded LiOH.H₂O (18 mg, 0.42 mmol) and water (0.5 mL). The reactionmixture was stirred overnight at 15° C., neutralized with 1 N HCl, andevaporated. The residue was dissolved in water (5 mL), extracted withethyl acetate (10 mL×2), dried over sodium sulfate, filtered, andevaporated to offer Compound 200D.

To a solution of Compound 200D (58 mg, 0.25 mmol) in CH₂Cl₂ (5 mL) wasadded Intermediate C (74 mg, 0.25 mmol) and HATU (142 mg, 0.375 mmol).The reaction mixture was stirred overnight at 15° C., evaporated andpurified with prep-HPLC to offer Compound 200. LC-MS: (m/z) 512 [M+1]⁺;¹H-NMR (CD₃OD, 400 MHz) major characteristic peaks: δ (ppm) 1.71 (br,6H), 1.95-2.07 (m, 4H), 2.18-2.21 (m, 2H), 3.52-3.53 (m, 4H), 3.64-3.71(m, 4H), 4.21-4.30 (m, 5H), 4.88-4.89 (m, 2H), 6.76-6.82 (m, 2H),6.91-6.93 (m, 2H), 7.57-7.63 (m, 2H).

Example 201

To a solution of Compound 197C (2.89 g, 10 mmol) in DCM (120 mL) wasadded dropwise DAST (4 mL) at room temperature. The mixture was stirredat room temperature overnight. Then it was quenched with ice, extractedwith DCM (30 mL×3), washed with water (50 mL×3) and brine (50×2 mL),dried over anhydrous sodium sulfate, and evaporated to obtain Compound201A.

Lithium hydroxide (420 mg, 10 mmol) was added to a solution of Compound201A (1.55 g, 5 mmol) in EtOH (20 mL) and water (5 mL). The reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas added 1 N HCl to adjust to pH 7 and concentrated in vacuum. Theresidue was extracted with EA (50 mL×3), dried over anhydrous sodiumsulfate, and concentrated to furnish Compound 201B.

A mixture of Compound 201B (141 mg, 0.5 mmol), Intermediate A (139 mg,0.5 mmol), HATU (380 mg, 1 mmol) in DMF (5 mL) was stirred at 25° C. for16 h. Then it was diluted with DCM (70 mL), washed with water (50 mL×3)and brine (50×2 mL), dried over anhydrous sodium sulfate, concentrated,and purified with prep-HPLC to obtain Compound 201. LC-MS (m/z): 543[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)1.71-1.80 (m, 4H), 2.64-2.69 (m, 4H), 2.94 (d, J=4.4 Hz, 2H), 4.14 (m,1H), 4.22 (m, 4H), 5.02 (s, 1H), 6.71-6.73 (m, 1H), 6.78-6.82 (m, 3H),6.98-7.07 (m, 7H), 7.30-7.32 (m, 1H).

Example 202

To a solution of 5-bromo-1H-indazole, 202A, (4.92 g, 25.0 mmol) in THF(300 mL) at 0° C. was added NaH (1.10 g, 27.5 mmol). The reactionsolution was stirred at this temperature for 1 hour before methyl iodide(5.32 g, 37.5 mmol) was added at 0° C. The reaction was allowed to warmto room temperature slowly, stirred for 2 hours, and quenched with waterand concentrated in vacuo. The residue was diluted with water andextracted with dichloromethane (80 mL×2). The organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated. Thecrude product was purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 202Band Compound 202C.

A mixture of Compound 178C (153 mg, 0.47 mmol), 202B (100 mg, 0.47mmol), Pd(dppf)₂Cl₂ (20 mg, 0.02 mmol), and K₂CO₃ (195 mg, 1.41 mmol) indioxane (3 mL) and water (3 mL) was stirred under nitrogen at 100° C.for 3 h. The reaction mixture was cooled to room temperature, anddiluted with ethyl acetate (50 mL). The mixture was filtered throughcelite, then the filtrate was treated with water (40 mL), extracted withethyl acetate (50 mL×2). The water layer was purified with flashchromatography to furnish the Compound 202D.

A mixture of Compound 202D (90 mg, 0.30 mmol), EDCI.HCl (86 mg, 0.45mmol), HOBt (61 mg, 0.45 mmol), and Intermediate G (93 mg, 0.30 mmol) inDCM (5 mL) was stirred for 18 h at 10° C. Then the mixture was dilutedby ethyl acetate (50 mL), washed with water (50 mL×2) and brine (50 mL),and dried over anhydrous sodium sulfate. After evaporation, the crudeproduct was purified with prep-HPLC to furnish Compound 202. LC-MS(m/z): 595 [M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) major characteristic peaks: δ(ppm) 0.49-0.51 (m, 4H), 2.03-2.17 (m, 4H), 3.16-3.31 (m, 2H), 3.51-3.74(m, 5H), 4.11 (s, 3H), 4.64 (d, J=10.4 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H),7.12 (dd, J=8.8, 1.2 Hz, 1H), 7.36-7.38 (m, 3H), 7.65-7.71 (m, 3H), 7.79(dd, J=8.8, 1.6 Hz, 1H), 8.08-8.09 (m, 2H).

Example 203

A mixture of Compound 197D (131 mg, 0.5 mmol), Intermediate C (154 mg,0.5 mmol), HATU (380 mg, 1 mmol) in DMF (5 mL) was stirred at 25° C. for16 h. Then it was diluted with DCM (20 mL), washed with water (50 mL×3)and brine (50×2 mL), dried over anhydrous sodium sulfate, concentrated,and purified with prep-HPLC to obtain Compound 203. LC-MS (m/z): 539[M+1]⁺; ¹H-NMR (CDCl₃, 400 MHz) major characteristic peaks: δ (ppm)2.08-2.19 (m, 4H), 2.87-3.04 (m, 4H), 3.45-3.56 (m, 2H), 3.87 (m, 1H)4.20-4.28 (m, 4H), 4.47 (m, 1H), 5.05 (s, 1H), 6.71-6.76 (m, 2H),6.87-6.98 (m, 4H), 6.98-7.05 (m, 1H), 7.27 (m, 1H), 7.35-7.42 (m, 1H),7.65 (s, 1H), 7.90-7.93 (m, 1H), 11.77 s, 1H).

Example 204

A mixture of Intermediate S (88 mg, 0.30 mmol), Compound 140B (78 mg,0.30 mmol), EDCI.HCl (86 mg, 0.45 mmol), and HOBt (60 mg, 0.45 mmol) indichloromethane (10 mL) was stirred at 10° C. for 15 h. Then it wastreated with water (20 mL), extracted with dichloromethane (20 mL×3),dried over anhydrous sodium sulfate, concentrated in vacuum, andpurified with prep-HPLC to obtain Compound 204. LC-MS (m/z): 543 [M+1]⁺;¹H-NMR (CDCl₃, 400 MHz) δ (ppm) 0.49-0.62 (m, 4H), 2.04 (s, 2H), 2.18(s, 2H), 3.17 (s, 1H), 3.27 (s, 1H), 3.54-3.71 (m, 4H), 3.78 (s, 1H),4.58 (d, J=12 Hz, 1H), 4.89 (s, 1H), 6.95 (d, J=8 Hz, 1H), 7.04 (t, J=8Hz, 2H), 7.22 (t, J=8 Hz, 2H), 7.39 (d, J=8 Hz, 2H), 7.63 (d, J=8 Hz,2H), 7.72 (t, J=8 Hz, 2H).

Example 205

A mixture of Compound 175B (288 mg, 0.95 mmol), 202B (200 mg, 0.95mmol), Pd(dppf)Cl₂ (40 mg, 0.05 mmol), and K₂CO₃ (393 mg, 2.85 mmol) indioxane (5 mL) and water (5 mL) was stirred under nitrogen at 90° C. for3 h. The reaction mixture was cooled to room temperature, and dilutedwith ethyl acetate (50 mL). The mixture was filtered through celite,then the filtrate was treated with water (40 mL), extracted with ethylacetate (50 mL×2). The water layer was adjusted to pH 3 by aqueous HClsolution (3 N), extracted with ethyl acetate (50 mL×2) and the ethylacetate layer was washed with water (50 mL×2), dried over sodiumsulfate, filtered, and concentrated to furnish the Compound 205A.

A mixture of Compound 205A (120 mg, 0.43 mmol), HATU (247 mg, 0.65mmol), and Intermediate G (133 mg, 0.43 mmol) in DMF (5 mL) was stirredfor 18 h at 10° C. Then the mixture was purified with prep-HPLC tofurnish Compound 205. LC-MS (m/z): 573 [M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz)major characteristic peaks: δ (ppm) 0.71-0.83 (m, 4H), 2.05-2.23 (m,4H), 3.24-3.34 (m, 2H), 3.59-3.88 (m, 5H), 4.12 (s, 3H), 4.72-4.75 (m,1H), 5.02 (d, J=2.4 Hz, 1H), 7.40 (s, 2H), 7.50 (s, 1H), 7.67-7.75 (m,5H), 7.81 (dd, J=8.8, 1.2 Hz, 1H), 8.12-8.13 (m, 2H).

Example 206

A mixture of Compound 133D (141 mg, 0.5 mmol), Intermediate G (155 mg,0.5 mmol), and HATU (380 mg, 1 mmol) in DMF (5 mL) was stirred at 25° C.overnight. The reaction mixture was diluted with DCM (70 mL), washedwith water (30 mL) and brine (30 mL), dried over anhydrous sodiumsulfate, and concentrated. The residue was purified with prep-HPLC tofurnish Compound 206. LC-MS (ESI) m/z: 575 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.66-0.81 (m, 4H), 2.00-2.15 (m, 4H), 3.12-3.23 (m, 2H),3.51-3.65 (m, 3H), 3.73-3.77 (m, 2H), 4.54 (m, 1H), 4.87 (s, 1H),7.02-7.07 (m, 5H), 7.10-7.15 (m, 4H), 7.30 (s, 1H), 7.38 (m, 1H).

Example 207

A mixture of Compound 205A (144 mg, 0.51 mmol), HATU (293 mg, 0.77mmol), and Intermediate A (142 mg, 0.51 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The reaction mixture was diluted with ethyl acetate(50 mL), washed with water (30 mL) and brine (30 mL), dried overanhydrous sodium sulfate, evaporated, and purified with prep-HPLC toyield Compound 207. LC-MS (ESI) m/z: 541 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 2.01-2.24 (m, 4H), 3.19-3.31 (m, 2H), 3.52-3.56 (m, 1H),3.68-3.72 (m, 2H), 3.81-3.88 (m, 1H), 4.10-4.21 (m, 7H), 4.65-4.69 (m,1H), 4.87 (s, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.91-6.94 (m, 1H), 6.97 (d,J=2.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.79-7.83 (m, 3H), 7.87-7.89 (m,2H), 8.12-8.13 (m, 2H).

Example 208

A mixture of Intermediate S (118 mg, 0.40 mmol), Compound 133D (97 mg,0.40 mmol), and HATU (228 mg, 0.60 mmol) in dichloromethane (10 mL) wasstirred at 30° C. for 15 h. Then it was treated with water (20 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuum, and purified with prep-HPLC to obtainCompound 208. LC-MS (m/z): 521 [M+1]⁺; ¹H-NMR (CD₃OD, 400 MHz) δ (ppm)0.67-0.82 (m, 4H), 2.05 (s, 2H), 2.21 (s, 2H), 3.10-3.27 (m, 2H),3.56-3.60 (m, 1H), 3.68-3.74 (m, 2H), 3.80-3.88 (m, 2H), 4.70 (d, J=8Hz, 1H), 4.98 (s, 1H), 7.19-7.27 (m, 4H), 7.37 (t, J=8 Hz, 1H), 7.68 (d,J=8 Hz, 2H), 7.72-7.78 (m, 4H).

Example 209

A mixture of Compound 209A (1.0 g, 4.85 mmol), magnesium chips (0.17 g,7.0 mmol) and THF (15 mL) was stirred at 50° C. for 1 h, and diethyloxalate (3 mL) was added. The mixture was stirred at 60° C. for 3 h, andsaturated NH₄Cl solution (10 mL) was added. It was extracted with ethylacetate (50 mL×2), washed with brine (50 mL), dried over anhydroussodium sulfate, and concentrated. The crude product was purified flashwith column chromatography on silica gel (10% ethyl acetate in petroleumether) to afford Compound 209B.

To a solution of Compound 209B (1.4 g, 6.1 mmol) in THF (15 mL) wasadded LiOH (390 mg, 9.0 mmol) in water (15 mL) at −10° C., and themixture was stirred at this temperature for 5 h. The reaction mixturewas treated with ice water (20 mL) and extracted with ethyl acetate (50mL). The water layer was adjusted to pH 2 with 1 M HCl and extractedwith ethyl acetate (50 mL×2). The combined organic layers were washedwith brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated. The resulting solid was washed with petroleum ether andfiltered to furnish the crude Compound 209C.

A mixture of Compound 209C (160 mg, 0.8 mmol), HATU (608 mg, 1.6 mmol),DMF (6.5 mL), and Intermediate G (298 mg, 0.96 mmol) in DCM (8 mL) wasstirred at room temperature overnight. The reaction mixture was treatedwith water (20 mL), extracted with DCM (50 mL×2), washed with brine (50mL), dried over anhydrous sodium sulfate, and concentrated. The crudeproduct was purified with prep-HPLC to afford Compound 209. LC-MS (ESI)m/z: 493 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.5-0.75 (m, 4H),2.06-2.21 (m, 4H), 3.26-3.30 (m, 1H), 3.58-3.82 (m, 6H), 4.73 (d, J=8.0Hz, 1H), 5.0 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H),7.51 (s, 1H), 7.57-7.71 (m, 2H), 7.84-7.95 (m, 4H), 8.26 (s, 1H).

Example 210

A mixture of Compound 201B (141 mg, 0.5 mmol), Intermediate C (148 mg,0.5 mmol), and HATU (380 mg, 1 mmol) in DMF (5 mL) was stirred at 25° C.for 16 h. The mixture was diluted with DCM (70 mL), and washed withwater (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate,and concentrated. The residue was purified with prep-HPLC to yieldCompound 210. LC-MS (ESI) m/z: 561 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 2.00-2.15 (m, 4H), 3.14-3.26 (m, 2H), 3.50-3.64 (m, 3H), 3.75 (m,1H), 4.21-4.23 (m, 4H), 4.54 (m, 1H), 4.79 (s, 1H), 6.60-6.63 (m, 2H),7.05-7.09 (m, 5H), 7.15-7.17 (m, 2H), 7.34 (t, J=8.0 Hz, 1H).

Example 211

A mixture of Compound 211A (10.00 g, 42.37 mmol), 4-fluorophenylboronicacid (5.51 g, 42.37 mol), PdCl₂(PPh₃)₂ (1.49 g, 2.12 mmol), and sodiumbicarbonate (10.68 g, 127.11 mmol) in dioxane (150 mL) and water (30 mL)was stirred at 90° C. for 16 h. It was adjusted to pH 1 with aqueous HClsolution (6 N, 10 mL). The mixture was extracted with dichloromethane(100 mL×3). The combined organic phases were washed with water (200 mL)and brine (200 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (methanol indichloromethane, from 0% to 8% v/v) to yield Compound 211B.

To a solution of Compound 211B (2.00 g, 7.97 mmol) in THF (50 mL) wasadded LiAH₄ (303 mg, 7.97 mmol) carefully. The mixture was stirred at25° C. for 16 h. The reaction mixture was quenched slowly with ice water(4 mL), filtered, and concentrated. The residue was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 0% to 50% v/v) to afford Compound 211C.

To a solution of Compound 211C (4.30 g, 20.57 mmol) in DCM (100 mL) wasadded Dess-Martin periodinane (9.60 g, 22.63 mmol) carefully. Themixture was stirred at 25° C. for 16 h. The mixture was filtered toremove the solid and concentrated. The residue was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 0% to 20% v/v) to afford Compound 211D.

To a solution of Compound 211D (1.80 g, 3.69 mmol) and NaCN (352 mg,17.39 mmol) in methanol (20 mL) was added AcOH (222 mg, 3.69 mmol)carefully. The mixture was stirred at 25° C. for 16 h, quenched with icewater to form a solid, filtered, and dried to afford Compound 211E.

A mixture of Compound 211E (1.20 g, 5.13 mmol) in methanol (20 mL) underHCl gas was stirred at 20° C. for 16 h. The reaction mixture wasquenched with ice water and extracted with dichloromethane (50 mL×3).The combined organic phases were washed with water (150 mL) and brine(150 mL), dried over anhydrous sodium sulfate, and evaporated to furnishCompound 211F.

To a solution of Compound 211F (1.20 g, 4.49 mmol) in DCM (20 mL) wasadded Dess-Martin periodinane (1.91 g, 4.49 mmol) carefully. The mixturewas stirred at 25° C. for 16 h. The mixture was filtered to remove thesolid. The filtrate was concentrated and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 0%to 30% v/v) to yield Compound 211G.

To a solution of Compound 211G (1.00 g, 3.80 mmol) in DCM (10 mL) wasadded dropwise DAST (3.06 g, 19.00 mmol). The mixture was stirred at 25°C. for 16 h and concentrated. The residue was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 0%to 15% v/v) to furnish Compound 211H.

A solution of Compound 211H (900 mg, 3.14 mmol) and aqueous LiOH H₂Osolution (1 N, 4.7 mL, 4.70 mmol) in THF (10 mL) was stirred at 25° C.for 2 h. The mixture was adjusted to pH 1 with aqueous HCl solution (6N, 5 mL), diluted with ice water (50 mL) to form a solid, filtered, anddried to yield Compound 2111.

A mixture of Compound 2111 (100 mg, 0.37 mmol), Intermediate A (102 mg,0.37 mmol), EDCI (106 mg, 0.56 mmol), and HOBt (76 mg, 0.56 mmol) indichloromethane (5 mL) and triethylamine (0.2 mL) was stirred at 25° C.for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL),washed with water (30 mL) and brine (30 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with prep-HPLC to furnish Compound211. LC-MS (ESI) m/z: 534 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm)1.92-2.13 (m, 4H), 3.12-3.22 (m, 2H), 3.55-3.65 (m, 3H), 3.72-3.78 (m,1H), 4.12 (s, 4H), 4.50-4.55 (m, 1H), 4.80 (s, 1H), 6.64 (d, J=8.4 Hz,1H), 6.75-6.81 (m, 2H), 7.26 (t, J=8.8 Hz, 2H), 7.85 (s, 1H), 8.04-8.08(m, 2H).

Example 212

A mixture of Compound 202D (50 mg, 0.16 mmol), EDCI (48 mg, 0.25 mmol),HOBt (34 mg, 0.25 mmol), and Intermediate A (28 mg, 0.26 mmol) in DCM (5mL) was stirred at 10° C. for 18 h. The mixture was diluted with ethylacetate (50 mL), washed with water (50 mL×2) and brine (50 mL), anddried over anhydrous sodium sulfate. After evaporation, the crudeproduct was purified with prep-HPLC to afford Compound 212. LC-MS (ESI)m/z: 563 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 2.02-2.18 (m, 4H),3.14-3.24 (m, 2H), 3.53-3.65 (m, 3H), 3.77-3.84 (m, 1H), 4.06 (s, 4H),4.12 (s, 3H), 4.55-4.57 (m, 1H), 4.82 (d, J=3.2 Hz, 1H), 6.65 (d, J=8.4Hz, 1H), 6.74 (dd, J=8.4, 2.0 Hz, 2H), 6.77 (d, J=2.0 Hz, 1H), 7.45 (d,J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.80 (dd,J=8.8, 1.6 Hz, 1H), 8.08-8.09 (m, 1H), 8.10 (d, J=1.2 Hz, 1H).

Example 213

A mixture of Compound 2111 (100 mg, 0.37 mmol), Intermediate G (115 mg,0.37 mmol), HOBt (76 mg, 0.56 mmol), and EDCI (106 mg, 0.56 mmol) indichloromethane (5 mL) and triethylamine (0.2 mL) was stirred at ambienttemperature for 16 hours. The reaction mixture was diluted with ethylacetate (120 mL), washed with water (100 mL) and brine (100 mL), driedover anhydrous sodium sulfate, concentrated, and purified with prep-HPLCto afford Compound 213. LC-MS (ESI) m/z: 566 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 0.62-0.75 (m, 4H), 1.96-2.14 (m, 4H), 3.13-3.26 (m, 2H),3.60-3.67 (m, 4H), 3.73-3.78 (m, 1H), 4.54-4.58 (m, 1H), 4.88 (s, 1H),7.14 (d, J=8.4 Hz, 1H), 7.24-7.29 (m, 3H), 7.34 (s, 1H), 7.85 (s, 1H),8.04-8.08 (m, 2H).

Example 214

A mixture of Compound 195A (150 mg, 0.66 mmol), Intermediate G (205 mg,0.66 mmol), HATU (500 mg, 1.32 mmol), and DIPEA (0.2 mL) in DMF (20 mL)was stirred at 25° C. for 16 h. The reaction mixture was diluted withethyl acetate (50 mL), washed with water (20 mL×3) and brine (20 mL),dried over anhydrous sodium sulfate, concentrated, and purified withprep-HPLC and chiral HPLC to furnish the desired product, which wasfurther purified with prep-HPLC to yield Compound 214. LC-MS (ESI) m/z:520 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.62-0.81 (m, 4H),2.05-2.23 (m, 4H), 3.15-3.28 (m, 2H), 3.58-3.85 (m, 5H), 4.69-4.72 (m,1H), 4.99 (m, 1H), 7.09-8.06 (m, 10H), 8.72 (m, 1H).

Example 215

A mixture of Compound 215A (2.05 g, 14.6 mmol), 2-bromothiazole (2 g,12.2 mmol), K₂CO₃ (3.12 g, 24.4 mmol) and Pd(PPh₃)₂Cl₂ (856 mg, 1.22mmol) in dioxane (40 mL) and water (4 mL) was stirred at 80° C. for 2 h.The mixture was cooled to room temperature, diluted with water (50 mL),extracted with ethyl acetate (100 mL). The ethyl acetate layer waswashed with water (100 mL×3) and brine (100 mL), dried over anhydroussodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to afford Compound 215B.

To a solution of Compound 215B (1.4 g, 7.8 mmol) in THF (30 mL) wasadded n-BuLi (3.4 mL, 8.6 mmol) dropwise at −78° C. The mixture wasstirred for 15 min and diethyl oxalate (2.28 g, 15.6 mmol) was added at−78° C. The mixture was stirred for 1 h. The reaction mixture wasdiluted with ethyl acetate (100 mL), washed with water (50 mL×3) andbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated toafford Compound 215C.

To a solution of Compound 215C (400 mg, 1.43 mmol) in THF (10 mL) andwater (1 mL) was added LiOH (90 mg, 2.15 mmol). The mixture was stirredat room temperature overnight, diluted with water (50 mL), and extractedwith ethyl acetate (50 mL). The aqueous layer was adjusted to pH 2 with1 M HCl. The precipitate was collected with filtration and dried tofurnish Compound 215D.

To a mixture of Compound 215D (97 mg, 0.386 mmol) in DCM (2 mL) wasadded HATU (176 mg, 0.463 mmol) and Intermediate G (120 mg, 0.386 mmol).The mixture was stirred at room temperature overnight. The mixture wastreated with water (50 mL), extracted with DCM (50 mL×2), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to afford Compound 215. LC-MS (ESI) m/z: 544[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.61-0.66 (m, 2H), 0.76-0.82(m, 2H), 1.80-1.88 (m, 2H), 1.96-2.03 (m, 2H), 3.09-3.17 (m, 2H),3.30-3.37 (m, 1H), 3.47-3.60 (m, 3H), 3.87-3.91 (m, 1H), 4.41-4.47 (m,1H), 4.79-4.80 (m, 1H), 6.02-6.07 (m, 1H), 7.28-7.45 (m, 5H), 8.14-8.18(m, 2H), 8.63 (d, J=9.2 Hz, 1H), 8.81 (s, 1H), 9.10-9.18 (m, 1H).

Example 216

To a solution of Compound 202B (400 mg, 1.89 mmol) in THF (10 mL) wasadded n-BuLi (2.5 N, 0.76 mL) under nitrogen at −78° C., and theresultant mixture was stirred for 30 min. And then diethyl oxalate (0.65mL, 4.73 mmol) was added to above mixture, and the resultant mixture wasstirred at −78° C. for 1 h. The mixture was quenched with saturatedaqueous NH₄Cl solution (10 mL), and extracted with ethyl acetate (50mL×2), washed with saturated aqueous sodium bicarbonate solution (50mL×2) and brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated to furnish Compound 216A.

To a solution of Compound 216A (490 mg, 2.11 mmol) in methanol (5 mL)was added a solution of LiOH H₂O (177 mg, 4.22 mmol) in water (5 mL),and the mixture was stirred at room temperature overnight. The crudeproduct was purified with reverse phase chromatography using eluent(methanol in water, from 0% to 7% v/v) to furnish Compound 216B.

A mixture of Compound 216B (100 mg, 0.49 mmol), HATU (279 mg, 0.74mmol), and Intermediate A (136 mg, 0.49 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was purified with prep-HPLC to affordCompound 216. LC-MS (ESI) m/z: 465 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 2.03-2.07 (m, 2H), 2.18-2.22 (m, 2H), 3.22-3.27 (m, 2H), 3.54-3.58(m, 1H), 3.67-3.73 (m, 2H), 3.79-3.85 (m, 1H), 4.03-4.24 (m, 7H),4.68-4.71 (m, 1H), 4.92 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.93 (dd,J=8.4, 2.0 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.96(dd, J=8.8, 1.6 Hz, 1H), 8.11 (s, 1H), 8.20 (s, 1H).

Example 217

A mixture of Compound 216B (100 mg, 0.49 mmol), HATU (279 mg, 0.74mmol), and Intermediate C (138 mg, 0.49 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was purified with prep-HPLC to affordCompound 217. LC-MS (ESI) m/z: 483 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 2.03-2.07 (m, 2H), 2.20-2.22 (m, 2H), 3.20-3.29 (m, 2H), 3.55-3.59(m, 1H), 3.67-3.73 (m, 2H), 3.78-3.84 (m, 1H), 4.08-4.13 (m, 4H),4.20-4.31 (m, 3H), 4.68-4.71 (m, 1H), 4.90 (d, J=2.4 Hz, 1H), 6.82-6.86(m, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.96 (dd, J=8.8, 1.6 Hz, 1H), 8.17 (s,1H), 8.19 (s, 1H).

Example 218

To a solution of Compound 180B (88 mg, 0.32 mmol) in DMF (10 mL) wasadded EDCI (93 mg, 0.48 mmol), HOBt (65 mg, 0.48 mmol) and IntermediateG (100 mg, 0.32 mmol). The mixture was stirred at 25° C. overnight. Thereaction mixture was quenched with saturated sodium bicarbonate solution(5 mL) and extracted with ethyl acetate (50 mL×3). The combined organicphases were washed with water (5 mL) and brine (5 mL), dried overanhydrous sodium sulfate, filtered, and concentrated. The crude productwas purified with prep-HPLC to furnish Compound 218. LC-MS (ESI) m/z:565 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.54-0.56 (m, 2H),0.63-0.64 (m, 2H), 2.03-2.05 (m, 2H), 2.16-2.18 (m, 2H), 3.18-3.26 (m,2H), 3.54-3.59 (m, 2H), 3.66-3.72 (m, 2H), 3.78-3.79 (m, 1H), 4.61-4.64(m, 1H), 4.91 (s, 1H), 7.05 (d, J=3.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H),7.17-7.21 (m, 3H), 7.24 (d, J=3.6 Hz, 1H), 7.34 (d, J=1.2 Hz, 1H),7.67-7.70 (m, 2H).

Example 219

To a solution of Intermediate G (136 mg, 0.44 mmol) in DMF (10 mL) wasadded Compound 174E (110 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol), andDIPEA (114 mg, 0.88 mmol). The mixture was stirred at 25° C. overnight.The reaction mixture was quenched with saturated sodium bicarbonatesolution (5 mL) and extracted with ethyl acetate (50 mL×3). The combinedorganic phases were washed with water (5 mL) and brine (5 mL), driedover anhydrous sodium sulfate, filtered, and concentrated. The crudeproduct was purified with prep-HPLC to afford Compound 219. LC-MS (ESI)m/z: 543 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.62-0.66 (m, 2H),0.73-0.78 (m, 2H), 2.00-2.04 (m, 2H), 2.16-2.19 (m, 2H), 3.19-3.28 (m,2H), 3.48-3.52 (m, 1H), 3.65-3.79 (m, 4H), 4.52-4.54 (m, 1H), 4.91 (s,1H), 7.22 (t, J=8.8 Hz, 2H), 7.32 (s, 2H), 7.41 (s, 1H), 7.48 (t, J=2.4Hz, 1H), 7.78-7.82 (m, 2H), 8.11 (d, J=4.4 Hz, 1H).

Example 220

A mixture of Compound 205A (56 mg, 0.20 mmol), Intermediate C (59 mg,0.20 mmol), and HATU (119 mg, 0.30 mmol) in DMF (10 mL) was stirred at10° C. for 2 h. The reaction mixture was treated with water (10 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuo, and purified with prep-HPLC to yieldCompound 220. LC-MS (ESI) m/z: 559 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.88 (s, 2H), 2.03 (s, 2H), 3.09-3.21 (m, 2H), 3.45 (d, J=8 Hz,2H), 3.56 (s, 2H), 4.09 (s, 3H), 4.28 (s, 4H), 4.51 (s, 1H), 4.78 (s,1H), 6.81 (t, J=16 Hz, 2H), 7.80 (q, J=12 Hz, 2H), 7.91 (dd, J=12, 4 Hz,4H), 8.17 (s, 2H), 8.74 (d, J=8 Hz, 1H).

Example 221

A mixture of Compound 2111 (100 mg, 0.37 mmol), Intermediate C (110 mg,0.37 mmol), HOBt (76 mg, 0.56 mmol), and EDCI (106 mg, 0.56 mmol) indichloromethane (5 mL) and triethylamine (0.2 mL) was stirred at ambienttemperature for 16 hours. The reaction mixture was diluted with ethylacetate (120 mL), washed with water (100 mL) and brine (100 mL), driedover anhydrous sodium sulfate, concentrated, and purified with prep-HPLCto afford Compound 221. LC-MS (ESI) m/z: 552 [M+H]⁺; ¹H-NMR (CD₃OD, 400MHz): δ (ppm) 1.95-2.14 (m, 4H), 3.14-3.31 (m, 2H), 3.58-3.64 (m, 3H),3.72-3.78 (m, 1H), 4.17 (s, 4H), 4.52-4.56 (m, 1H), 4.82 (s, 1H),6.85-6.70 (m, 2H), 7.24-7.29 (m, 2H), 7.91 (s, 1H), 8.05-8.09 (m, 2H).

Example 222

To a solution of Compound 215C (1.0 g, 3.58 mmol) in DCM (20 mL) wasadded DAST (2.89 g, 17.9 mmol) and the mixture was stirred at 30° C.overnight. The mixture was diluted with DCM (100 mL), washed with water(50 mL×3) and brine (50 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 222A.

To a solution of Compound 222A (1.04 g, 3.45 mmol) in THF (20 mL) andwater (2 mL) was added LiOH (217 mg, 5.18 mmol). The mixture was stirredat room temperature overnight, diluted with water (50 mL), and adjustedto pH 2 with 1M HCl. The precipitate was collected with filtration anddried to furnish Compound 222B.

To a mixture of Compound 222B (100 mg, 0.366 mmol) in DCM (2 mL) wasadded HATU (167 mg, 0.44 mmol) and Intermediate G (114 mg, 0.366 mmol).The mixture was stirred at room temperature overnight. The mixture wastreated with water (50 mL), extracted with DCM (50 mL×2), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to afford Compound 222. LC-MS (ESI) m/z: 566[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.51-0.53 (m, 2H), 0.66-0.67(m, 2H), 1.85-1.90 (m, 2H), 1.98-2.02 (m, 2H), 3.10-3.21 (m, 2H),3.42-3.53 (m, 4H), 3.63-3.67 (m, 1H), 4.45-4.51 (m, 1H), 4.80 (s, 1H),5.98-6.01 (m, 1H), 7.14-7.18 (m, 2H), 7.26 (s, 1H), 7.39-7.43 (m, 2H),7.94 (s, 1H), 8.02-8.05 (m, 2H), 8.89 (d, J=9.2 Hz, 1H), 9.38-9.47 (m,1H).

Example 223

A mixture of Compound 205A (56 mg, 0.20 mmol), Intermediate H (56 mg,0.20 mmol), and HATU (119 mg, 0.30 mmol) in DMF (10 mL) was stirred at10° C. for 2 h. The reaction mixture was treated with water (10 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuo, and purified with prep-HPLC to yieldCompound 223. LC-MS (ESI) m/z: 545 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 2.26 (s, 1H), 2.42 (t, J=8 Hz, 1H), 3.44-3.48 (m, 2H), 4.09 (s,3H), 4.19-4.43 (m, 9H), 4.74 (s, 1H), 6.80 (t, J=16 Hz, 2H), 7.81-7.87(m, 6H), 8.17 (s, 2H), 8.74 (d, 2H), 9.63 (brs, 2H).

Example 224

A mixture of Compound 216B (100 mg, 0.49 mmol), HATU (279 mg, 0.74mmol), and Intermediate G (152 mg, 0.49 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was purified with prep-HPLC to affordCompound 224. LC-MS (ESI) m/z: 497 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.59-0.83 (m, 4H), 2.04-2.23 (m, 4H), 3.24-3.27 (m, 1H), 3.34-3.35(m, 1H), 3.59-3.82 (m, 5H), 4.11 (s, 3H), 4.73-4.77 (m, 1H), 5.01 (s,1H), 7.34 (d, J=8.8 Hz, 1H), 7.40 (dd, J=8.4, 1.6 Hz, 1H), 7.49 (d,J=2.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.99 (s,1H), 8.15 (s, 1H).

Example 225

To a mixture of LDA (2 N, 8.3 mL, 16.5 mmol) in tetrahydrofuran (10 mL)under nitrogen was added Compound 225A (3.2 g, 15.0 mmol) intetrahydrofuran (5 mL) slowly at −78° C. It was stirred at −78° C. for 1h, and the mixture was added to a solution of carbon tetrachloride (5.5mL, 56.6 mmol) in tetrahydrofuran (15 mL) at −78° C. The resultantmixture was stirred at −78° C. for 1.5 h, quenched with ammoniumchloride solution (50 mL), warmed to room temperature, and extractedwith DCM (100 mL×2). The combined organic phases were washed with water(50 mL) and brine (50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified with flash columnchromatography on silica gel (petroleum ether, 100% v/v) to furnishCompound 225B.

A solution of Compound 225B (1.2 g, 5 mmol) in THF (10 mL) undernitrogen was added n-BuLi (2.4 N, 2.5 mL, 6 mmol) at −78° C. The mixturewas stirred at −78° C. for 30 min. To the above mixture was addeddiethyl oxalate (5 mL). The resultant solution was stirred at −78° C.for 15 min, quenched with saturated aqueous NH₄Cl solution (10 mL), andextracted with ethyl acetate (50 mL×2). The combined organic phases werewashed with water (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified with flashcolumn chromatography on silica gel (petroleum ether, 100% v/v) toafford Compound 225C.

To a solution of Compound 225C (268 mg, 1 mmol) in MeOH (5 mL) was addeda solution of LiOH H₂O (126 mg, 3 mmol) in water (2 mL). The mixture wasstirred at room temperature overnight. The solution was concentrated toremove methanol, adjusted to pH 2 with HCl (6 N, 2 mL), and extractedwith ethyl acetate (50 mL×2). The combined organic phases were washedwith water (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 10% to 20% v/v) to furnish Compound 225D.

A mixture of Compound 225D (125 mg, 0.5 mmol), HATU (342 mg, 0.9 mmol),and Intermediate G (162 mg, 0.5 mmol) in DMF (2 mL) and DCM (5 mL) wasstirred at 25° C. overnight. The mixture was concentrated, and purifiedwith prep-HPLC to yield Compound 225. LC-MS (ESI) m/z: 533 [M+H]⁺;¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.65-.090 (m, 4H), 1.97-2.23 (m, 4H),3.12-3.27 (m, 1H), 3.58-3.62 (m, 1H), 3.69-3.85 (m, 5H), 4.60-4.63 (m,1H), 5.01 (s, 1H), 7.37-7.52 (m, 4H), 7.52 (s, 1H), 7.68 (d, J=8.0 Hz,1H), 7.84 (d, J=8.0 Hz, 1H).

Example 226

A solution of Compound 211G (500 mg, 1.89 mmol) and LiOH.H₂O (119 mg,2.83 mmol) in THF (10 mL) and water (2 mL) was stirred at −10° C. for 1h. It was diluted with ice water (20 mL) and adjusted to pH 1 withdiluted hydrochloric acid (6 M) to form a solid. The mixture wasfiltered and the resulting solid was dried to yield Compound 226A.

A mixture of Compound 226A (100 mg, 0.40 mmol), Intermediate C (118 mg,0.40 mmol), and HATU (228 mg, 0.60 mmol) in DMF (3 mL) was stirred atroom temperature for 16 h. It was diluted with ethyl acetate (120 mL),washed with water (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, concentrated, and purified with prep-HPLC to affordCompound 226. LC-MS (ESI) m/z: 530 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.84 (brs, 2H), 1.99 (brs, 2H), 3.08-3.16 (m, 2H), 3.38-3.54 (m,4H), 4.25 (s, 4H), 4.45 (t, J=6.0 Hz, 1H), 4.76 (s, 1H), 6.14 (brs, 1H),6.74 (s, 1H), 6.81 (d, J=11.6 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 8.08-8.12(m, 2H), 8.80 (d, J=9.6 Hz, 1H), 8.96 (s, 1H), 9.37 (brs, 1H).

Example 227

A mixture of Compound 200D (46 mg, 0.20 mmol), Intermediate H (63 mg,0.20 mmol), and HATU (119 mg, 0.30 mmol) in DMF (10 mL) was stirred at10° C. for 3 h. The reaction mixture was treated with water (10 mL),extracted with dichloromethane (20 mL×3), dried over anhydrous sodiumsulfate, concentrated in vacuo, and purified with prep-HPLC to yieldCompound 227. LC-MS (ESI) m/z: 498 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 1.22 (s, 2H), 1.66 (s, 6H), 3.44-3.48 (m, 5H), 3.67 (d, J=12 Hz,1H), 4.15-4.33 (m, 9H), 4.90 (s, 1H), 6.69 (d, J=12 Hz, 2H), 6.76 (d,J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H).

Example 228

A mixture of Compound 195A (100 mg, 0.44 mmol), Intermediate C (130 mg,0.44 mmol), and HATU (335 mg, 0.88 mmol) in DMF (10 mL) was stirred atroom temperature overnight. The reaction mixture was diluted with ethylacetate (50 mL), washed with water (20 mL×3) and brine (20 mL), driedover anhydrous sodium sulfate, concentrated, and purified with prep-HPLCto yield Compound 228. LC-MS (ESI) m/z: 506 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 1.73-1.75 (m, 4H), 2.54-2.68 (m, 6H), 4.31-4.33 (m, 5H),4.76-4.77 (s, 1H), 5.69 (s, 1H), 6.75 (s, 1H), 6.81 (d, J=10.4 Hz, 1H),7.45-7.46 (m, 1H), 7.83-7.98 (m, 3H), 8.07-8.08 (m, 1H), 8.19-8.20 (m,2H), 8.63-8.64 (m, 1H), 8.74-8.75 (m, 1H).

Example 229

A mixture of Compound 226A (100 mg, 0.40 mmol), Intermediate A (111 mg,0.40 mmol), and HATU (228 mg, 0.60 mmol) in DMF (3 mL) was stirred atroom temperature for 16 h. It was diluted with ethyl acetate (120 mL),washed with water (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, concentrated, and purified with prep-HPLC to affordCompound 229. LC-MS (ESI) m/z: 512 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.83 (brs, 2H), 1.99 (brs, 2H), 3.06-3.17 (m, 2H), 3.37-3.53 (m,4H), 4.18 (s, 4H), 4.43 (t, J=11.2 Hz, 1H), 4.74 (s, 1H), 5.99 (brs,1H), 6.77-6.87 (m, 3H), 7.40 (t, J=8.8 Hz, 2H), 8.08-8.12 (m, 2H), 8.80(d, J=9.6 Hz, 1H), 8.95 (s, 1H), 9.24 (brs, 1H).

Example 230

To a solution of Compound 174E (62 mg, 0.25 mmol) in DMF (5 mL) wasadded Intermediate C (74 mg, 0.25 mmol) and HATU (141 mg, 0.37 mmol).The reaction mixture was stirred at 25° C. for 16 h. The mixture waspurified with prep-HPLC to yield Compound 230. LC-MS (m/z) 529 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.14-2.17 (m, 4H), 2.77-2.87 (m, 2H),3.11-3.14 (m, 2H), 3.49-3.51 (m, 1H), 3.82-3.92 (m, 3H), 4.15-4.19 (m,3H), 4.89 (brs, 1H), 5.16 (s, 1H), 6.70-6.74 (m, 2H), 7.07-7.11 (m, 2H),7.24-7.25 (m, 1H), 7.59-7.63 (m, 2H), 8.03-8.06 (m, 1H), 8.16-8.17 (m,1H), 9.70 (brs, 1H).

Example 231

To a solution of Compound 200D (100 mg, 0.43 mmol) in DMF (5 mL) wasadded Intermediate G (151 mg, 0.43 mmol) and HATU (151 mg, 0.43 mmol).The reaction mixture was stirred at 15° C. overnight. The mixture waspurified with prep-HPLC to give Compound 231. LC-MS (m/z) 526 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.77-0.79 (m, 4H), 1.66 (s, 6H),2.04-2.08 (m, 4H), 3.34-3.51 (m, 10H), 3.72-3.74 (m, 1H), 4.49-4.51 (m,1H), 5.15 (s, 1H), 6.70-6.73 (m, 2H), 7.20-7.24 (m, 1H), 7.36 (s, 1H),7.75-7.77 (m, 1H), 7.89-7.91 (m, 2H).

Example 232

To Compound 232A (10 g, 50.8 mmol) in THF (50 mL) was added sodiumhydride (60% in mineral, 2.2 g, 55.8 mmol) with ice bath cooling. Themixture was stirred at room temperature for 30 min. Methyl iodide (4.74mL, 76.1 mmol) was added at room temperature. The reaction mixture wasstirred at room temperature for 1 h, quenched with saturated aqueousammonium chloride solution (30 mL), and extracted with ethyl acetate(100 mL×3). The combined organic layers were washed with brine (200 mL),dried over anhydrous sodium sulfate, and concentrated. Purification withflash column chromatography on silica gel (ethyl acetate in petroleumether, 10% to 30% v/v) gave Compound 232B and Compound 232C.

A mixture of Compound 232B (600 mg, 2.84 mmol), Compound 178B (926 mg,2.84 mmol), Pd(dppf)Cl₂ (116 mg, 0.14 mmol), and K₂CO₃ (1.18 g, 8.52mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was diluted with water (50 mL) andextracted with ethyl acetate (50 mL×2), and then the organic layer wasdiscarded off. The aqueous layer was acidified to pH 3 with aqueous HClsolution (1 N) and extracted with ethyl acetate (100 mL×2). The combinedorganic layers were washed with water (50 mL×2) and brine (50 mL), driedover anhydrous sodium sulfate, and concentrated to give Compound 232D.

A mixture of Compound 232D (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol),HOBt (68 mg, 0.5 mmol), and Intermediate G (102 mg, 0.33 mmol) indichloromethane (5 mL) was stirred at 10° C. for 18 h. The mixture wasdiluted with ethyl acetate (50 mL), washed with water (50 mL×2) andbrine (50 mL), and dried over anhydrous sodium sulfate. Afterevaporation, the crude product was purified with prep-HPLC to furnishCompound 232. LC-MS (ESI) m/z: 595 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.33-0.41 (m, 4H), 1.95-2.08 (m, 4H), 3.08-3.17 (m, 2H), 3.38-3.64(m, 4H), 3.70-3.72 (m, 1H), 4.05 (s, 3H), 4.54-4.56 (m, 1H), 4.82 (d,J=2.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.8, 1.6 Hz, 1H),7.28-7.30 (m, 3H), 7.42 (d, J=9.2 Hz, 1H), 7.66 (d, J=7.6 Hz, 2H),7.75-7.77 (m, 2H), 7.95 (s, 1H).

Example 233

To a solution of Compound 233A (1.0 g, 4.7 mmol) in THF (30 mL) wasadded magnesium chips (0.23 g, 9.4 mmol) at room temperature. Themixture was stirred at 50° C. for 2 h, and then diethyl oxalate (3 mL)was added in one portion. The mixture was stirred at 60° C. for 3 h. Thesolution was quenched with saturated NH₄Cl solution and extracted withethyl acetate (50 mL×2). The combined organic phases were washed withwater (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate,filtered, and concentrated. The crude product was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,10% v/v) to give Compound 233B.

To a solution of Compound 233B (1.4 g, 6.1 mmol) in THF (15 mL) wasadded LiOH H₂O (390 mg, 9.0 mmol) in water (15 mL) at −10° C., and themixture was stirred at this temperature for 5 hours. The reactionmixture was treated with ice water (20 mL) and extracted with ethylacetate (50 mL). The water layer was adjusted to pH 2 with diluted HCland extracted with ethyl acetate (50 mL×2). The combined organic layerswere washed with brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated. The resulting solid was washed with petroleum ether andfiltered off to furnish the crude Compound 233C.

A mixture of Compound 233C (160 mg, (0.8 mmol), HATU (608 mg, 1.6 mmol),DMF (6.5 mL) and Intermediate G (298 mg, 0.96 mmol) in DCM (8 mL) wasstirred at room temperature overnight. The reaction mixture was treatedwith water (20 mL), extracted with DCM 50 mL×2), washed with brine (50mL), dried over anhydrous sodium sulfate, and concentrated. The crudeproduct was purified with prep-HPLC to give Compound 233. LC-MS (ESI)m/z: 499.1 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.61-0.79 (m, 4H),2.01-2.23 (m, 4H), 3.21-3.30 (m, 1H), 3.58-3.86 (m, 6H), 4.73 (d, J=10.8Hz, 1H), 5.00 (s, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H),7.47 (d, J=5.2 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.73-7.75 (m, 2H), 7.98(d, J=8.4 Hz, 1H), 8.15 (s, 1H).

Example 234

A mixture of Compound 133D (156 mg, 0.50 mmol), Intermediate D (100 mg,0.45 mmol), and HATU (285 mg, 0.75 mmol) in dichloromethane (10 mL) wasstirred at 10° C. for 15 h. And then it was treated with water (10 mL)and extracted with dichloromethane (10 mL×3 mL). The organic layers werewashed with water (20 mL×3), dried over anhydrous sodium sulfate,concentrated in vacuo, and purified with prep-HPLC to furnish Compound234. LC-MS (ESI) m/z: 539 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.09(s, 4H), 3.06 (s, 2H), 3.46 (s, 1H), 3.73 (t, J=12 Hz, 1H), 3.89 (s,2H), 4.10-4.19 (m, 4H), 4.43 (s, 1H), 4.99 (s, 1H), 6.76 (s, 1H), 6.92(s, 1H), 7.08 (t, J=8 Hz, 2H), 7.50 (t, J=8 Hz, 4H), 7.67 (d, J=8 Hz,2H), 7.80 (d, J=8 Hz, 2H), 8.50 (s, 1H).

Example 235

A mixture of Compound 232D (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol),HOBt (68 mg, 0.5 mmol), and Intermediate A (92 mg, 0.33 mmol) indichloromethane (5 mL) was stirred at 10° C. for 18 h. The mixture wasdiluted with ethyl acetate (50 mL), washed with water (50 mL×2) andbrine (50 mL), and dried over anhydrous sodium sulfate. Afterevaporation, the crude product was purified with prep-HPLC to furnishCompound 235. LC-MS (ESI) m/z: 563 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 2.03-2.17 (m, 4H), 3.15-3.24 (m, 2H), 3.53-3.67 (m, 3H), 3.80-3.82(m, 1H), 4.07 (s, 4H), 4.15 (s, 3H), 4.56-4.58 (m, 1H), 4.83 (d, J=3.2Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.72-6.79 (m, 2H), 7.47-7.53 (m, 3H),7.81 (d, J=8.0 Hz, 2H), 7.86-7.88 (m, 2H), 8.05 (s, 1H).

Example 236

A mixture of Compound 232D (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol),HOBt (68 mg, 0.5 mmol), and Intermediate C (98 mg, 0.33 mmol) indichloromethane (5 mL) was stirred at 10° C. for 18 h. The mixture wasdiluted with ethyl acetate (50 mL), washed with water (50 mL×2) andbrine (50 mL), and dried over anhydrous sodium sulfate. Afterevaporation, the crude product was purified with prep-HPLC to furnishCompound 236. LC-MS (ESI) m/z: 581 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 2.03-2.18 (m, 4H), 3.17-3.27 (m, 2H), 3.53-3.81 (m, 4H), 4.01-4.07(m, 4H), 4.15 (s, 3H), 4.59-4.62 (m, 1H), 4.84 (d, J=2.8 Hz, 1H), 6.59(s, 1H), 6.68 (dd, J=11.6, 2.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.52 (d,J=8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.86-7.88 (m, 2H), 8.05 (s, 1H).

Example 237

A mixture of Compound 232C (200 mg, 0.95 mmol), Compound 178C (310 mg,0.95 mmol), Pd(dppf)Cl₂ (39 mg, 0.05 mmol), and K₂CO₃ (393 mg, 2.85mmol) in dioxane (3 mL) and water (3 mL) was stirred under nitrogen at100° C. for 4 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was treated with water (50 mL) andextracted with ethyl acetate (50 mL×2). The aqueous layer was acidifiedto pH 3 with aqueous HCl solution (1 N) and extracted with ethyl acetate(100 mL×2). The combined organic layers were washed with water (50 mL×2)and brine (50 mL), dried over anhydrous sodium sulfate, and concentratedto give Compound 237A.

A mixture of Compound 237A (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol),HOBt (68 mg, 0.5 mmol), and Intermediate G (102 mg, 0.33 mmol) indichloromethane (5 mL) was stirred at 10° C. for 18 h. The mixture wasdiluted with ethyl acetate (50 mL), washed with water (50 mL×2) andbrine (50 mL), and dried over anhydrous sodium sulfate. Afterevaporation, the crude product was purified with prep-HPLC to furnishCompound 237. LC-MS (ESI) m/z: 595 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.45-0.54 (m, 4H), 2.04-2.18 (m, 4H), 3.17-3.32 (m, 2H), 3.49-3.81(m, 5H), 4.26 (s, 3H), 4.62-4.64 (m, 1H), 4.90 (s, 1H), 7.03 (d, J=8.4Hz, 1H), 7.11 (dd, J=8.4, 1.6 Hz, 1H), 7.37-7.40 (m, 3H), 7.47 (d, J=8.8Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.8 Hz, 1H), 7.90 (s, 1H),8.25 (s, 1H).

Example 238

A mixture of Compound 238A (1.72 g, 10 mmol), 1,5-dibromopentane (2.75g, 12 mmol), sodium dodecyl sulfate (SDS, cat. 40 mg), and sodiumbicarbonate (1 g, 12 mmol) in water (20 mL) was heated at 100° C. for1.5 hours. The reaction mixture was treated with water (20 mL) andextracted with ethyl acetate (50 mL×3). The extraction was washed withwater (50 mL), dried over anhydrous sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 0% to 1% v/v) to give Compound 238B.

To a solution of Compound 238B (2.4 g, 10 mmol) in dry THF (50 mL) wasadded dropwise LDA (2.0 M, 5.0 mL, 12.0 mmol) under nitrogen at −70° C.After stirring for 30 min., diethyl oxalate (2.19 g, 15.0 mmol) wasadded quickly. The mixture was stirred at −70° C. for about an hour. Itwas quenched with saturated ammonium chloride (10 mL) solution andextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed with water (5 mL) and brine (5 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to give a residue. The crude productwas purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, from 0% to 10% v/v) to afford Compound 238C.

To a solution of Compound 238C (261 mg, 1 mmol) in methanol (5 mL) wasadded dropwise lithium hydroxide (1 N, 2 mL, 2 mmol). The reactionmixture was stirred at room temperature for 2 h. After the reactionmixture was concentrated, HCl (2 N, 1 mL) was added to adjust pH 7,followed by extraction with ethyl acetate (50 mL×3). The combinedorganic phases were washed with water (5 mL) and brine (5 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to furnishCompound 238D.

To a solution of Compound 238D (100 mg, 0.429 mmol) in dichloromethane(3 mL) was added Intermediate G (130 mg, 0.429 mmol) and HATU (196 mg,0.515 mmol). The mixture was stirred at room temperature for 2 h. It wasconcentrated and the resulting residue was purified with prep-HPLC tofurnish Compound 238. LC-MS (ESI) m/z: 526 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 0.79-0.83 (m, 4H), 1.57-1.61 (m, 2H), 1.67-1.72 (m, 5H),1.85-1.87 (m, 4H), 2.71-2.92 (m, 4H), 2.96-3.07 (m, 2H), 3.17-3.19 (m,4H), 3.75-3.78 (m, 1H), 4.31-4.32 (m, 1H), 5.14 (d, J=1.6 Hz, 1H),7.16-7.23 (m, 2H), 7.24-7.37 (m, 3H), 7.58-7.60 (m, 1H), 7.76-7.78 (m,1H).

Example 239

To a solution of Compound 180B (68 mg, 0.25 mmol) in DMF (5 mL) wasadded Intermediate C (74 mg, 0.25 mmol) and HATU (142 mg, 0.37 mmol).The reaction mixture was stirred at 25° C. for 16 h. The mixture waspurified with prep-HPLC to yield Compound 239. LC-MS (m/z) 551 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.15-2.18 (m, 4H), 2.94-2.97 (m, 1H),3.06-3.10 (m, 1H), 3.50-3.53 (m, 2H), 3.82-3.88 (m, 2H), 4.08-4.10 (m,3H), 4.16-4.23 (m, 1H), 4.39-4.42 (m, 1H), 5.08 (brs, 1H), 6.59-6.67 (m,2H), 7.08-7.11 (m, 3H), 7.51-7.55 (m, 3H).

Example 240

To a solution of Compound 202C (158 mg, 0.75 mmol) in 1,4-dioxane (15mL) was added ethyl 178C (250 mg, 0.825 mmol), Pd(dppf)Cl₂ (30 mg,0.0375 mmol), potassium carbonate (310 mg, 2.25 mmol) and water (1 mL)under nitrogen. The reaction mixture was stirred at 100° C. for 2 hours.The resulting mixture was cooled to 25° C. The precipitated solid wasfiltered and dried to afford Compound 240A.

To a solution of Compound 240A (68 mg, 0.24 mmol) in DMF (3 mL) wasadded Intermediate C (71 mg, 0.24 mmol) and HATU (137 mg, 0.36 mmol).The reaction mixture was stirred at 10° C. overnight. The mixture waspurified with prep-HPLC to yield the product Compound 240. LC-MS (m/z)559 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 2.15-2.22 (m, 4H),2.94-2.95 (m, 2H), 3.08-3.09 (m, 2H), 3.49-3.50 (m, 1H), 3.56-3.57 (m,1H), 3.91-3.94 (m, 2H), 4.23-4.27 (m, 5H), 4.49-4.52 (m, 1H), 5.12-5.13(m, 1H), 6.73-6.78 (m, 2H), 7.58-7.61 (m, 1H), 7.69-7.71 (m, 2H),7.79-7.81 (m, 1H), 7.85-7.90 (m, 2H), 7.99 (s, 1H), 8.19-8.21 (m, 2H).

Example 241

To a solution of Compound 241A (3.1 g, 27.6 mmol) and potassiumcarbonate (4.15 g, 30.0 mmol) in DMF (50 mL) was added4-bromobenzaldehyde (5.0 g, 27.6 mmol). The reaction mixture was stirredat 130° C. for 12 h. The reaction was quenched with water (50 mL) andextracted with dichloromethane (150 mL×3). The combined organic layerswere washed with brine (150 mL), dried over anhydrous sodium sulfate,filtered, and evaporated. The remaining residue was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 0% to 10% v/v) to furnish Compound 241B.

A mixture of Compound 241B (1.9 g, 8.8 mmol), and sodium metabisulfite(3.3 g, 17.6 mmol) in water (40 mL) was pre-stirred for 1 h, and thenNaCN (431.2 mg, 8.8 mmol) was added into the above-mentioned mixture,and the whole reaction solution was stirred at room temperature for 12h. The reaction was treated with water (100 mL) and extracted with ethylacetate (100 mL×3). The combined organic layers were washed with brine(100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated.The crude product was purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, from 0% to 30% v/v) togive Compound 241C.

To a solution of Compound 241C (1.0 g, 27.6 mmol) in methanol (50 mL)was bubbled with HCl (gas), which was prepared with condensed H₂SO₄ andNaCl. After 4 h later, the reaction was quenched with water (50 mL) andextracted with dichloromethane (150 mL×3). The combined organic layerswere washed with brine (150 mL), dried over anhydrous sodium sulfate,filtered, and evaporated. The remaining residue was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 0% to 30% v/v) to afford Compound 241D.

To a solution of Compound 241D (170 mg, 0.62 mmol) in dichloromethane(15 mL) was added Dess-Martin periodinane (313 mg, 0.74 mmol). Thereaction was stirred at 0° C. for 0.5 h. The reaction was treated withwater (50 mL) and extracted with dichloromethane (150 mL×3). Thecombined organic layers were washed with brine (150 mL), dried overanhydrous sodium sulfate, filtered, and evaporated. The remainingresidue was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, 3% v/v) to furnish Compound 241E.

To a solution of Compound 241E (160 mg, 0.58 mmol) in methanol (15 mL)was added LiOH solution (1 N, 0.6 mL, 0.60 mmol). The reaction wasstirred at 0° C. for 0.5 h. The reaction was quenched with water (50 mL)and neutralized to pH 1 with HCl (1 M). The mixture was extracted withdichloromethane (150 mL×3). The combined organic layers were washed withbrine (150 mL), dried over anhydrous sodium sulfate, filtered, andevaporated to afford Compound 241F.

To a solution of Compound 241F (100 mg, 0.38 mmol) in a mixture ofdichloromethane (14 mL) and DMF (2 mL) was added Intermediate G (119 mg,0.38 mmol) and HATU (175 mg, 0.46 mmol). The mixture was stirred at roomtemperature for 12 h. The reaction was quenched with water (50 mL) andextracted with dichloromethane (150 mL×3). The combined organic layerswere washed with brine (150 mL), dried over anhydrous sodium sulfate,filtered, and evaporated. The remaining residue was purification withprep-HPLC to give Compound 241. LC-MS (ESI) m/z: 553 [M+H]⁺; ¹H-NMR(CDCl₃, 400 MHz): δ (ppm) 0.65-0.82 (m, 4H), 2.14 (s, 4H), 2.66-2.96 (m,4H), 3.51-3.90 (m, 4H), 4.54 (s, 1H), 5.12 (s, 1H), 6.88 (d, J=8.6 Hz,2H), 7.00-7.12 (m, 4H), 7.16-7.26 (m, 2H), 7.34-7.37 (m, 1H), 7.97-8.03(m, 3H), 11.60 (s, 1H).

Example 242

Compound 242A (2.44 g, 15.4 mmol) and potassium carbonate (2.76 g, 20.0mmol) were suspended in dry DMF (15 mL) and the resulting mixture wascooled to 0° C. Ethyl thioglycolate (1.7 mL, 15.5 mmol) was added inportions over 1 h and the reaction mixture was warmed slowly to roomtemperature and stirred at 25° C. for 16 h. The reaction was heated at60° C. for 5.5 h before cooling and adding water (30 mL). The resultingmixture was stirred at room temperature for 30 min and filtered. Theresidue was washed with water (5 mL×2) and dried to afford the Compound242B.

Compound 242B (500 mg, 2.08 mmol) was dissolved in hot ethanol (12 mL)and a solution of potassium hydroxide (642 mg, 11.5 mmol) in water (12mL) was added to the mixture. The suspension was heated at reflux for1.5 h during which time it mostly dissolved. After cooling slightlyaqueous HCl solution (6 N, 5 mL) was added dropwise. Ethanol wasevaporated in vacuo and the residual solid was filtered. The filteredcake was washed with water (20 mL) and dried to give Compound 242C.

Compound 242C (420 mg, 1.98 mmol) and copper powder (63 mg, 0.99 mmol)were suspended in quinoline (10 mL) and the resulting mixture was heatedat 185° C. for 2 h. After cooling down to room temperature, ethylacetate (25 mL) was added and the suspension was filtered. The filteredcake was washed with ethyl acetate (5 mL×2) and the combined organiclayers were washed with aqueous HCl solution (2 N, 10 mL×2). Afterdrying over anhydrous sodium sulfate, the solution was filtered andevaporated in vacuo to give a residue. The crude product was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, from 0% to 10% v/v) to afford Compound 242D.

To a solution of Compound 242D (310 mg, 1.85 mmol) in dry THF (20 mL)was added dropwise n-BuLi (2.4 M solution in hexane, 1.2 mL, 2.78 mmol)under nitrogen at −78° C. After stirring for 30 min, diethyl oxalate(808 mg, 5.54 mmol) was added quickly. The mixture was stirred at −78°C. for about an hour. The resulting mixture was quenched with saturatedaqueous NH₄Cl solution (5 mL), extracted with ethyl acetate (50 mL×3),washed with water (5 mL) and brine (5 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to yield a crude compound. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 242E.

To a solution of Compound 242E (150 mg, 0.56 mmol) in THF (10 mL) wasadded dropwise a solution of LiOH H₂O (25 mg, 0.62 mmol) in water (2.5mL) at −30° C. The mixture was stirred at −30° C. for half an hour. Thereaction solution was adjusted to pH 3 with aqueous HCl solution (1 N,2.5 mL) and separated. The organic layer was dried directly overanhydrous sodium sulfate, filtered, and concentrated to afford Compound242F.

To a solution of Intermediate G (129 mg, 0.42 mmol) in DMF (10 mL) wasadded Compound 242F (100 mg, 0.42 mmol), HATU (237 mg, 0.62 mmol), andN, N-diisopropylethylamine (107 mg, 0.83 mmol) under nitrogen. Themixture was stirred at 25° C. overnight. The resulting mixture wasquenched with saturated aqueous sodium bicarbonate solution (5 mL) andextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed with water (5 mL) and brine (5 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to afford a crude compound. Thecrude product was purified with prep-HPLC to furnish Compound 242. LC-MS(ESI) m/z: 533 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.58-0.70 (m,2H), 0.73-0.79 (m, 2H), 2.01-2.04 (m, 2H), 2.16-2.21 (m, 2H), 3.20-3.26(m, 2H), 3.49-3.53 (m, 1H), 3.70-3.76 (m, 4H), 4.58-4.60 (m, 1H), 4.91(d, J=2.8 Hz, 1H), 7.32-7.34 (m, 2H), 7.44 (d, J=1.6 Hz, 1H), 7.47 (dd,J=8.8, 2.0 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 8.38 (s, 1H).

Example 243

A mixture of Compound 232C (600 mg, 2.84 mmol), Compound 175B (863 mg,2.84 mmol), Pd(dppf)Cl₂ (116 mg, 0.14 mmol), and K₂CO₃ (1.18 g, 8.52mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was treated with water (50 mL) andextracted with ethyl acetate (50 mL×2). The aqueous layer was acidifiedto pH 3 with aqueous HCl solution (1 N) and filtered. The cake waswashed with water (20 mL) and dried in vacuo to give Compound 243A.

A mixture of Compound 243A (100 mg, 0.36 mmol), HATU (205 mg, 0.54mmol), and Intermediate A (112 mg, 0.36 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was purified with prep-HPLC to furnishCompound 243. LC-MS (ESI) m/z: 573 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.72-0.82 (m, 4H), 2.07-2.08 (m, 2H), 2.23-2.24 (m, 2H), 3.31-3.32(m, 2H), 3.60-3.63 (m, 1H), 3.71-3.77 (m, 2H), 3.83-3.89 (m, 2H),4.15-4.16 (m, 3H), 4.72-4.76 (m, 1H), 5.02 (s, 1H), 7.41 (s, 2H), 7.50(s, 1H), 7.53-7.55 (m, 1H), 7.70-7.72 (m, 2H), 7.79-7.81 (m, 2H),7.88-7.89 (m, 2H), 8.07 (s, 1H).

Example 244

To a solution of Compound 232C (800 mg, 3.79 mmol) in dry THF (10 mL)was added n-BuLi (2.5 N solution in hexane, 1.53 mL) under nitrogen at−78° C. The resulting solution was stirred at −78° C. for 30 min andtransferred into a stirred solution of diethyl oxalate (1.39 g, 9.5mmol) in dry THF (5 mL) at −78° C. The solution was stirred at −78° C.for 1 h, quenched with addition of saturated NH₄Cl solution (10 mL),poured into water (100 mL), and extracted with ethyl acetate (50 mL×2).The combined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate, and concentrated in vacuo to give a solid.This solid was triturated with methanol and filtered. The filtrate wasconcentrated to give the desired Compound 244A which was used for thenext step without further purification.

To a solution of Compound 244A (500 mg, 2.16 mmol) in methanol (10 mL)was added a solution of LiOH.H₂O (200 mg, 4.32 mmol) in water (5 mL).The mixture was stirred at room temperature overnight and purified withreverse phase chromatography using eluent (methanol in water, from 0% to7% v/v) to furnish Compound 244B.

A mixture of Compound 244B (70 mg, 0.34 mmol), HATU (194 mg, 0.51 mmol),and Intermediate G (105 mg, 0.34 mmol) in DMF (5 mL) was stirred at 10°C. for 18 h. The mixture was purified with prep-HPLC to afford Compound244. LC-MS (ESI) m/z: 497 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)0.62-0.82 (m, 4H), 1.88-1.91 (m, 2H), 2.03-2.05 (m, 2H), 3.13-3.20 (m,2H), 3.47-3.59 (m, 4H), 3.89-3.90 (m, 1H), 4.14 (s, 3H), 4.54-4.56 (m,1H), 4.86 (d, J=2.8 Hz, 1H), 7.33-7.39 (m, 2H), 7.45-7.49 (m, 2H), 7.84(d, J=8.8 Hz, 1H), 8.21 (s, 1H), 8.27 (s, 1H), 8.83 (d, J=9.2 Hz, 1H),9.32 (brs, 1H).

Example 245

A mixture of Compound 244B (60 mg, 0.29 mmol), HATU (167 mg, 0.44 mmol),and Intermediate C (86 mg, 0.29 mmol) in DMF (5 mL) was stirred at 10°C. for 18 h. The mixture was purified with prep-HPLC to afford Compound245. LC-MS (ESI) m/z: 483 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)1.87-2.04 (m, 4H), 3.08-3.21 (m, 2H), 3.43-3.46 (m, 2H), 3.54-3.57 (m,2H), 4.12 (s, 3H), 4.22-4.32 (m, 4H), 4.48-4.55 (m, 1H), 4.77 (d, J=2.8Hz, 1H), 6.77 (s, 1H), 6.84 (dd, J=11.6, 1.6 Hz, 1H), 7.51 (dd, J=8.4,0.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 8.21 (s, 1H), 8.31 (s, 1H), 8.81(d, J=9.2 Hz, 1H), 9.31 (brs, 1H).

Example 246

A mixture of Compound 243A (100 mg, 0.36 mmol), HATU (205 mg, 0.54mmol), and Intermediate C (107 mg, 0.36 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was purified with prep-HPLC to furnishCompound 246. LC-MS (ESI) m/z: 559 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.73-1.74 (m, 4H), 2.54-2.61 (m, 5H), 2.66-2.71 (m, 1H), 4.13 (s,3H), 4.27-4.31 (m, 5H), 4.78 (d, J=2.8 Hz, 1H), 6.76 (s, 1H), 6.83 (dd,J=11.2, 1.2 Hz, 1H), 7.52 (dd, J=8.4, 1.2 Hz, 1H), 7.79-7.92 (m, 5H),8.05 (s, 1H), 8.11 (s, 1H), 8.66 (d, J=9.6 Hz, 1H).

Example 247

A mixture of Compound 247A (14.2 g, 50 mmol), Compound(4-fluorophenyl)boronic acid (7.7 g, 55 mmol), Pd(dppf)Cl₂ (2.05 g, 2.5mmol) and K₂CO₃ (20.7 g, 150 mmol) in dioxane (600 mL) and water (80 mL)was heated to reflux for 2 h. Ethyl acetate (500 mL) was added. Theorganic layers were washed with water (50 mL), saturated sodiumbicarbonate solution (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, and concentrated to give a crude compound. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 5% to 10% v/v) to furnishCompound 247B.

To a solution of Compound 247B (2.51 g, 10 mmol) in THF (20 mL) wasadded n-BuLi (4.4 mL, 2.4 M in hexane, 11 mmol) dropwise under nitrogenat −76° C. The reaction mixture was stirred at −76° C. for 15 minutes.The reaction was added to a solution of diethyl oxalate (4.7 mL, 35mmol) in THF (10 mL) under nitrogen at −60° C. for 30 minutes. Thereaction mixture was quenched with saturated NH₄Cl solution (10 mL) andwater (50 mL) and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were washed with brine (25 mL), dried over anhydroussodium sulfate, filtered, and evaporated to give a crude compound. Thecrude product was purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 5% to 10% v/v) to furnishCompound 247C.

To a solution of Compound 247C (445 mg, 1.64 mmol) in drydichloromethane (10 mL) was added DAST (0.55 mL, 4.09 mmol). The mixturewas stirred at 25° C. for 14 hours. After the reaction was completed,dichloromethane (35 mL) was added. The organic layer was washed withwater (20 mL), saturated sodium bicarbonate solution (20 mL) and brine(20 mL), dried over anhydrous sodium sulfate, and concentrated to give acrude compound. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 10%to 20% v/v) to furnish Compound 247D.

To a solution of Compound 247D (458 mg, 1.57 mmol) in THF/water/MeOH (9mL, 1:1:1, v/v) was added LiOH.H₂O (98 mg, 2.35 mmol). The mixture wasstirred at 28° C. for 1 h. After the reaction was completed, it wasadjusted to pH 6 with 2 N HCl. The reaction mixture was concentrated invacuo. The crude product was in lyophilization to furnish Compound 247E.

A mixture of Compound 247E (88 mg, 0.33 mmol), Intermediate G (128 mg,0.41 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) indichloromethane (15 mL) and DMF (2 mL) was stirred at 25° C. for 5 h. Itwas treated with water (20 mL), extracted with dichloromethane (20mL×3), dried over anhydrous sodium sulfate, concentrated in vacuo, andpurified with prep-HPLC to furnish Compound 247. LC-MS (ESI) m/z: 560[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.65-0.68 (m, 4H), 2.12-2.15(m, 4H), 3.00-3.02 (m, 2H), 3.38-3.45 (m, 2H), 3.53-3.62 (m, 2H),3.75-3.82 (m, 2H), 4.50-4.52 (m, 1H), 4.94-4.96 (d, J=2.8 Hz, 1H), 7.07(s, 2H), 7.20 (t, J=8.8 Hz, 2H), 7.32-7.34 (m, 1H), 7.65-7.71 (m, 2H),8.00-8.04 (m, 2H), 8.68 (s, 1H).

Example 248

A mixture of Compound 197D (52 mg, 0.20 mmol), Intermediate H (63 mg,0.20 mmol), and HATU (119 mg, 0.30 mmol) in DMF (5 mL) was stirred at10° C. for 3 h. The mixture was purified with prep-HPLC to furnishCompound 248. LC-MS (ESI) m/z: 525 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 2.34-2.46 (m, 1H), 2.55-2.66 (m, 1H), 3.34 (s, 1H), 3.41-3.47 (m,1H), 3.56 (dd, J=8, 12 Hz, 1H), 4.07-4.15 (s, 5H), 4.22-4.29 (m, 3H),4.85 (s, 1H), 6.62-6.63 (m, 2H), 6.66-7.02 (m, 4H), 7.13 (d, J=8 Hz,1H), 7.31 (t, J=8 Hz, 1H), 7.52 (t, J=8 Hz, 2H).

Example 249

To a mixture of Compound 197D (130 mg, 0.5 mmol) and intermediate G (148mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith reverse phase chromatography using eluent (methanol in water, from10% to 50% v/v) to furnish Compound 249. LC-MS (ESI) m/z: 553 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.67-0.68 (m, 2H), 0.81-0.82 (m, 2H),1.63-1.69 (m, 4H), 2.462-2.468 (m, 2H), 2.56-2.63 (m, 4H), 3.91-3.92 (m,1H), 4.21-4.25 (m, 1H), 4.80 (s, 1H), 5.69 (s, 1H), 7.11-7.13 (m, 2H),7.27-7.54 (m, 9H), 8.64-8.66 (d, J=8.6 Hz, 1H).

Example 250

A mixture of Compound 250A (5.0 g, 27 mmol), 4-fluorophenylboronic acid(4.92 g, 35.13 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.19 g,1.62 mmol), potassium carbonate (11.2 g, 81.07 mmol), water (38 mL) and1,4-dioxane (38 mL) was stirred under nitrogen atmosphere at 120° C. for6 h. After cooling, water (20 mL) was added, and the mixture wasextracted with ethyl acetate (100 mL×3). The combined organic layerswere washed until neutral and dried over anhydrous sodium sulfate. Afterremoval of the solvent in vacuo, the crude product was purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, from 5% to 10% v/v) to furnish Compound 250B.

To a solution of Compound 250B (3.0 g, 14.98 mmol) in water (40 mL) wasadded sodium metabisulfite (2.85 g, 14.98 mmol). The reaction mixturewas stirred at room temperature for 1 h. After that, NaCN (1.47 g, 29.97mmol) was added carefully. The mixture was stirred for 12 h and treatedwith ethyl acetate (100 mL). The resulting biphasic mixture wastransferred to a separatory funnel. The layers were separated and theorganic phase was washed with water (20 mL) and brine (20 mL). Theorganic phase was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford the crude product, which was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, from 20% to 40% v/v)) to furnish Compound 250C.

To a solution of Compound 250C (2.5 g, 11 mmol) in methanol (25 mL) at0° C. was bubbled a gentle stream of HCl (gas) (dried over con. H₂SO₄)for 6 h. The reaction mixture was diluted with water (20 mL) and stirredat room temperature for 2 h. An aqueous solution of NaOH (2 M) was addeddropwise into the reaction mixture until the pH was adjusted to 7. Themixture was extracted with dichloromethane (50 mL×3) and washed withwater (50 mL) and brine (50 mL). The combined organic phases were driedover anhydrous sodium sulfate, filtered, and concentrated to give thecrude product. The crude compound was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 15%to 20% v/v) to furnish Compound 250D.

To a solution of Compound 250D (2.3 g, 8.84 mmol) in dichloromethane (30mL) was added 1,2-benziodoxol-3(1H)-one (2.41 g, 9.72 mmol) at 0° C. Themixture was stirred at this temperature for 4 h. After that, thereaction solution was quenched with saturated ammonium chloride solution(10 mL) and extracted with ethyl acetate (30 mL×3). The organic phasewas washed with water (20 mL) and brine (20 mL), dried over anhydroussodium sulfate, filtered, and concentrated to furnish the crude product.The crude oil was purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 5% to 10% v/v) to furnishCompound 250E.

To a solution of Compound 250E (1.80 g, 6.97 mmol) in THF (20 mL) wasadded LiOH.H₂O (335 mg, 7.98 mmol) in water (14 mL) at 0° C. The mixturewas stirred at room temperature for 1 h. The reaction mixture wastreated with ice water (10 mL) and extracted with ethyl acetate (50 mL).The water layer was adjusted to pH 2 with diluted HCl and extracted withethyl acetate (50 mL×2). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated.The resulting solid was washed with petroleum ether and filtered off toafford Compound 250F.

A mixture of Compound 250F (110 mg, 0.45 mmol), Intermediate C (146 mg,0.49 mmol), and HATU (205 mg, 0.54 mmol) in dichloromethane (3 mL) andDMF (3 mL) was stirred at 0° C. for 4 h. The mixture was concentrated invacuo and the resulting residue was purified with prep-HPLC to furnishthe crude product as a white solid. The crude solid was further purifiedwith prep-TLC on silica gel (ethyl acetate in petroleum ether, 30% v/v)to furnish Compound 250. LC-MS (ESI) m/z: 523 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 1.82-1.85 (m, 4H), 2.72-2.78 (m, 4H), 2.99-3.03 (m, 2H),4.23-4.31 (m, 5H), 5.05 (d, J=2.1, 1H), 6.70 (s, 1H), 6.74 (dd, J=11.3,1.9 Hz, 1H), 7.15 (t, J=8.7 Hz, 3H), 7.42-7.59 (m, 3H), 7.79 (d, J=8.3,1H), 8.20 (d, J=6.7, 1H), 8.44 (s, 1H). Chiral separation condition:n-hexane (0.1% DEA):EtOH (0.1% DEA)=30:60, column: OD-H (250*4.6 mm 5m), retention time: 4.09 mm.

Example 251

A mixture of Compound 250F (130 mg, 0.53 mmol), Intermediate G (182 mg,0.58 mmol), and HATU (304 mg, 0.79 mmol) in dichloromethane (3 mL) andDMF (3 mL) was stirred at 0° C. for 4 h. The mixture was concentrated invacuo and purified with prep-HPLC to furnish the crude product as ayellow solid. The crude solid was further purified with prep-TLC onsilica gel (ethyl acetate in petroleum ether, 30% v/v) to furnishCompound 251. LC-MS (ESI) m/z: 537 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ(ppm) 0.71 (dd, J=10.7, 4.5 Hz, 4H), 1.89 (s, 1H), 2.08 (s, 4H), 3.12(s, 2H), 3.48-3.71 (m, 2H), 3.83-3.94 (m, 3H), 4.55 (s, 1H), 5.07 (s,1H), 7.08-7.12 (m, 2H), 7.15-7.23 (m, 2H), 7.35 (d, J=1.8 Hz, 1H),7.38-7.49 (m, 3H), 7.71 (d, J=7.9 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.94(d, J=9.6 Hz, 1H), 8.12 (s, 1H).

Example 252

To a mixture of Compound 252A (1.8 g, 0.01 mol) and triethylamine (3 g,0.03 mol) in dichloromethane (100 mL) was added ethyl2-chloro-2-oxoacetate (2.1 g, 0.015 mol). The mixture was stirred atroom temperature for about 2 h until it was complete by thin layerchromatography analysis. The resulting mixture was washed with brine(100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, from 10% to 50% v/v) tofurnish Compound 252B.

To a solution of Compound 252B (2.8 g, 0.01 mol) in ethanol/water (40mL/10 mL) was added LiOH H₂O (840 mg, 0.02 mol). The mixture was stirredat room temperature for about 2 h until it was complete by thin layerchromatography analysis. The reaction mixture was acidified to pH 2 withaqueous HCl solution (1.0 N, 40 mL) and extracted with ethyl acetate (30mL×2). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated toafford Compound 252C.

To a mixture of Compound 252C (126 mg, 0.5 mmol) and Intermediate A (139mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith reverse phase chromatography using eluent (methanol in water, from10% to 55% v/v) to furnish Compound 252. LC-MS (ESI) m/z: 513 [M+H]⁺;¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 1.83-1.84 (m, 4H), 2.68-2.72 (m, 5H),2.88-2.94 (m, 2H), 3.03-3.06 (m, 2H), 3.09-3.14 (m, 1H), 3.33-3.37 (m,2H), 3.58-.366 (m, 1H), 3.75-3.81 (m, 1H), 4.20-4.21 (m, 4H), 4.37-4.39(m, 1H), 4.84-4.85 (m, 1H), 6.79-6.81 (m, 1H), 6.86-6.88 (m, 1H), 6.96(s, 1H), 7.01-7.04 (m, 4H);

Example 253

A mixture of Compound 133D (146 mg, 0.60 mmol), EDCI (193 mg, 0.90mmol), HOBt (119 mg, 0.9 mmol) and Intermediate I (178 mg, 0.60 mmol) inDCM (20 mL) was stirred at room temperature overnight. The reactionmixture was treated with water (50 mL), extracted with DCM (50 mL×2),washed with brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated. The crude product was purified with prep-HPLC to giveCompound 253. LC-MS (ESI) m/z: 523.1 [M+H]⁺, ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.71-0.84 (m, 4H), 2.45-2.66 (m, 2H), 3.57-3.67 (m, 2H), 3.84-3.86(m, 1H), 4.21-4.36 (m, 5H), 4.55-4.57 (m, 1H), 4.98 (d, J=2.4 Hz, 1H),7.21-7.28 (m, 2H), 7.35-7.40 (m, 2H), 7.52 (s, 1H), 7.64-7.67 (m, 4H),7.73-7.77 (m, 2H).

Example 254

To a mixture of Compound 252C (126 mg, 0.5 mmol) and Intermediate C (150mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The resulting residue waspurified with reverse phase chromatography using eluent (methanol inwater, from 10% to 55% v/v) to furnish Compound 254. LC-MS (ESI) m/z:531 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.86-2.01 (m, 4H),2.87-3.84 (m, 14H), 4.27 (s, 4H), 4.40-4.43 (m, 1H), 4.47 (s, 1H), 6.73(s, 1H), 6.80-6.81 (m, 1H), 6.83-6.85 (m, 2H), 7.06-7.18 (m, 2H), 8.68(d, J=9.6 Hz, 1H), 9.83 (brs, 1H).

Example 255

A mixture of Compound 255A (0.72 g, 2.8 mmol), K₃PO₄ (1.78 g, 8.4 mmol),(4-(tert-butyl)phenyl)boronic acid (0.5 g, 2.8 mmol), and Pd(dppf)Cl₂(20 mg, 0.28 mmol) in toluene (10 mL) was stirred under nitrogen at 100°C. for 16 h. The mixture was cooled to 25° C., diluted with ethylacetate (50 mL), washed with water (20 mL×2) and brine (20 mL), driedover anhydrous sodium sulfate, concentrated, and purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 0% to 10% v/v) to afford Compound 255B.

A mixture of Compound 255B (0.45 g, 1.5 mmol) and LiOH.H₂O (0.09 g, 2.2mmol) in THF (5 mL) and water (2 mL) was stirred at 0° C. for 2 h. Themixture was diluted with ethyl acetate (30 mL), washed with water (10mL×2) and brine (10 mL), dried over anhydrous sodium sulfate,concentrated, and purified with reverse phase chromatography usingeluent (methanol in water, from 0% to 100% v/v) to afford Compound 255C.

A mixture of Compound 255C (0.1 g, 0.35 mmol), HATU (0.2 g, 0.5 mmol),and Intermediate G in dichloromethane (5 mL) was stirred at 25° C. for16 h. The mixture was diluted with ethyl acetate (30 mL), washed withwater (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate,concentrated, and purified with prep-HPLC to furnish Compound 255. LC-MS(ESI) m/z: 575 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.67-0.68 (m,2H), 0.82-0.83 (m, 2H), 1.33 (s, 9H), 1.88-1.90 (m, 2H), 2.04 (s, 2H),3.13-3.23 (m, 2H), 3.48-3.56 (m, 4H), 3.93 (s, 1H), 4.54-4.59 (m, 1H),4.88 (s, 1H), 6.05 (s, 1H), 7.36-7.44 (m, 3H), 7.53-7.56 (m, 2H),7.68-7.77 (m, 6H), 8.78-8.81 (m, 1H), 9.36 (s, 1H).

Example 256

To 6-bromoindazole (3.2 g, 16.2 mmol) in DMF (30 mL) was added sodiumhydride (60% in mineral, 712 mg, 17.8 mmol) with ice bath cooling. Themixture was stirred at room temperature for 30 min. Compound2-iodopropane (8.3 g 48.6 mmol) was added at room temperature. Thereaction mixture was stirred at room temperature for 1 h, quenched withsaturated aqueous ammonium chloride solution (30 mL), and extracted withethyl acetate (100 mL×3). The combined organic layers were washed withbrine (200 mL), dried over anhydrous sodium sulfate, and concentrated.Purification with flash column chromatography on silica gel (ethylacetate in petroleum ether, from 0% to 1% v/v) gave Compound 256A andCompound 256B.

A mixture of Compound 256A (1.0 g, 4.2 mmol), Compound 175B (1.28 g, 4.2mmol), Pd(dppf)Cl₂ (171 mg, 0.21 mmol), and K₂CO₃ (1.74 g, 12.6 mmol) indioxane (20 mL) and water (20 mL) was stirred under nitrogen at 100° C.for 3.5 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was diluted with water (100 mL)and extracted with ethyl acetate (100 mL×2). The aqueous layer wasacidified to pH 3 with aqueous HCl solution (1 N) and extracted withethyl acetate (100 mL×2). The combined organic layers were washed withwater (100 mL×2) and brine (100 mL), dried over anhydrous sodiumsulfate, and concentrated to give Compound 256C.

A mixture of Compound 256C (100 mg, 0.32 mmol), HATU (182 mg, 0.48mmol), and Intermediate G (99 mg, 0.32 mmol) in DMF (5 mL) was stirredfor 18 h at 10° C. The mixture was diluted with ethyl acetate (50 mL),washed with water (50 mL×2) and brine (50 mL), and dried over anhydroussodium sulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 256. LC-MS (ESI) m/z: 601 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.63-0.85 (m, 4H), 1.52 (dd, J=6.4, 1.6 Hz,6H), 1.89-2.05 (m, 4H), 3.13-3.25 (m, 2H), 3.41-3.58 (m, 4H), 3.93-3.98(m, 1H), 4.57-4.62 (m, 1H), 4.91 (s, 1H), 5.12-5.18 (m, 1H), 6.10 (s,1H), 7.37 (dd, J=8.4, 1.6 Hz, 1H), 7.43-7.48 (m, 2H), 7.52 (dd, J=8.4,1.2 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.8 Hz, 3H), 8.09 (s,1H), 8.14 (s, 1H), 8.84 (d, J=9.6 Hz, 1H), 9.59 (brs, 1H).

Example 257

A mixture of Compound 175B (500 mg, 2.1 mmol), Compound 256B (638 mg,2.1 mmol), Pd(dppf)Cl₂ (92 mg, 0.11 mmol), and K₂CO₃ (869 mg, 6.3 mmol)in dioxane (10 mL) and water (10 mL) was stirred under nitrogen at 100°C. for 3.5 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was diluted with water (100 mL)and extracted with ethyl acetate (100 mL×2). The aqueous layer wasacidified to pH 3 with aqueous HCl solution (1 N) and extracted withethyl acetate (100 mL×2). The combined organic layers were washed withwater (100 mL×2) and brine (100 mL), dried over anhydrous sodiumsulfate, and concentrated to give Compound 257A.

A mixture of Compound 257A (100 mg, 0.32 mmol), HATU (182 mg, 0.48mmol), and Intermediate G (99 mg, 0.32 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was diluted with ethyl acetate (50 mL),washed with water (50 mL×2) and brine (50 mL), and dried over anhydroussodium sulfate. After evaporation, the crude product was purified withprep-HPLC to furnish Compound 257. LC-MS (ESI) m/z: 601 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.68-0.84 (m, 4H), 1.58 (d, J=6.4 Hz, 6H),1.89-2.04 (m, 4H), 3.09-3.22 (m, 2H), 3.43-3.58 (m, 4H), 3.93-3.97 (m,1H), 4.56-4.61 (m, 1H), 4.84-4.92 (m, 2H), 6.08-609 (m, 1H), 7.35-7.38(m, 1H), 7.41-7.46 (m, 3H), 7.75-7.77 (m, 2H), 7.82-7.85 (m, 3H), 8.01(s, 1H), 8.48 (s, 1H), 8.83 (d, J=10.0 Hz, 1H), 9.65 (brs, 1H).

Example 258

To a solution of 5-bromo-1H-indazole (5.91 g, 30 mmol) in anhydrous DMF(100 mL) was added 2-bromopropane (8.67 g, 70.5 mmol) and cesiumcarbonate (29.2 g, 90 mmol) at room temperature. After stirring thereaction mixture at room temperature for 3 h, 2 N hydrochloric acid wasadded until a neutral pH was reached. The aqueous layer was extractedwith ethyl acetate (100 mL×2). The combined organic extracts were washedwith brine (100 mL×2) and dried over anhydrous sodium sulfate. Afterfiltration, the solvent was removed in vacuo and the residue waspurified with flash column chromatography on silica gel to give Compound258A and Compound 258B.

To a solution of Compound 258A (180 mg, 0.75 mmol) in 1,4-dioxane (15mL) was added Compound 175B (250 mg, 0.825 mmol), Pd(dppf)Cl₂ (30 mg,0.0375 mmol), potassium carbonate (310 mg, 2.25 mmol) and water (1 mL)under nitrogen. The reaction mixture was stirred at 100° C. for 2 hours.The resulting mixture was cooled to 25° C. The precipitated solid wasfiltered and dried to afford Compound 258C.

To a solution of Compound 258C (45 mg, 0.146 mmol) in DMF (3 mL) wasadded Intermediate G (45 mg, 0.146 mmol) and HATU (83 mg, 0.219 mmol).The reaction mixture was stirred at 20° C. for 10 h. The mixture waspurified with prep-HPLC to yield the product Compound 258. LC-MS (m/z)601 [M+H]⁺; 1H-NMR (Acetone-d₆, 400 MHz): δ (ppm) 0.71-0.72 (m, 2H),0.82-0.84 (m, 2H), 1.57 (s, 3H), 1.58 (s, 3H), 2.05-2.25 (m, 4H),3.45-3.60 (m, 2H), 3.82-4.15 (m, 5H), 4.92-4.97 (m, 1H), 5.02-5.09 (m,1H), 5.20-5.21 (m, 1H), 5.47-5.50 (m, 1H), 7.42-7.44 (m, 2H), 7.51-7.52(m, 1H), 7.79-7.83 (m, 4H), 7.97-7.99 (m, 2H), 8.12-8.16 (m, 2H),8.19-8.21 (m, 1H), 8.94 (brs, 1H).

Example 259

To a solution of Compound 258B (180 mg, 0.75 mmol) in 1,4-dioxane (15mL) was added Compound 175B (250 mg, 0.825 mmol), Pd(dppf)Cl₂ (30 mg,0.0375 mmol), potassium carbonate (310 mg, 2.25 mmol) and water (1 mL)under nitrogen. The reaction mixture was stirred at 100° C. for 2 hours.The resulting mixture was cooled to 25° C. The precipitated solid wasfiltered and dried to afford Compound 259A.

To a solution of Compound 259A (74 mg, 0.24 mmol) in DMF (3 mL) wasadded Intermediate G (74 mg, 0.24 mmol) and HATU (136 mg, 0.36 mmol).The reaction mixture was stirred at 20° C. for 10 h. The mixture waspurified with prep-HPLC to yield the product Compound 259. LC-MS (m/z)601 [M+H]⁺; ¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 0.70-0.72 (m, 2H),0.79-0.84 (m, 2H), 1.68 (s, 3H), 1.70 (s, 3H), 2.05-2.13 (m, 2H),2.26-2.28 (m, 2H), 3.43-3.56 (m, 2H), 3.85-3.91 (m, 3H), 4.06-4.09 (m,2H), 4.93-5.01 (m, 2H), 5.20-5.21 (m, 1H), 7.39-7.46 (m, 2H), 7.51-7.52(m, 1H), 7.75-7.82 (m, 4H), 7.97-7.99 (m, 2H), 8.16-8.21 (m, 2H),8.58-8.59 (m, 1H), 8.82 (brs, 1H).

Example 260

To a mixture of Compound 247E (100 mg, 0.3 mmol) in THF (10 mL) and DMF(2 mL) was added EDCI (106 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) andIntermediate G (115 mg, 0.37 mmol). The mixture was stirred at 25° C.for 15 hours. It was diluted with water (20 mL) and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(25 mL), dried over anhydrous sodium sulfate, and concentrated to give acrude compound. The crude product was purified with prep-HPLC to affordCompound 260. LC-MS (ESI) m/z: 538 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.61-0.75 (m, 4H), 2.06-2.20 (m, 4H), 3.22-3.28 (m, 2H), 3.56-3.80(m, 5H), 4.61-4.64 (m, 1H), 4.94 (s, 1H), 7.21-7.31 (m, 4H), 7.41 (d,J=1.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.77-7.80 (m, 2H), 8.19 (dd,J=8.0, 2.0 Hz, 1H), 8.82 (s, 1H).

Example 261

A suspension of Compound 261A (6.00 g, 30.15 mmol) and SeO₂ (5.02 g,45.22 mmol) in pyridine (50 mL) was stirred at 100° C. for 16 h. It wasfiltered to remove the resultant solid and the filtrate was evaporatedto remove pyridine. The residue was dissolved in aqueous NaOH solution(5% w/w, 200 mL) and extracted with diethyl ether (100 mL×2). Theaqueous was adjusted to pH 1 with con. HCl to form a solid, which wasfiltered and dried to afford Compound 261B.

A mixture of Compound 261B (3.00 g, 13.22 mmol) and concentrated H₂SO₄(1 mL) in methanol (50 mL) was stirred at 80° C. for 16. Afterevaporation, the residue was diluted with ethyl acetate (200 mL), washedwith water (200 mL) and brine (200 mL), dried over anhydrous sodiumsulfate, and purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 0% to 10% v/v) to furnishCompound 261C.

A mixture of Compound 261C (1.58 g, 6.53 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.82 g,7.18 mmol), KOAc (1.92 g, 19.59 mmol), and PdCl₂(PPh₃)₂ (229 mg, 0.33mmol) in dioxane (50 mL) was stirred under nitrogen at 90° C. for 16 h.It was diluted with ethyl acetate (150 mL), washed with water (200 mL)and brine (200 mL), dried over anhydrous sodium sulfate, and evaporatedto afford Compound 261D.

A mixture of Compound 261D (500 mg, 1.72 mmol),6-bromo-1-methyl-1H-indazole (364 mg, 1.72 mmol), K₂CO₃ (475 mg, 3.44mmol), and Pd(dppf)Cl₂ (70 mg, 0.09 mmol) in dioxane (10 mL) and water(2 mL) was stirred under nitrogen at 85° C. for 16 h. The mixture wascooled down to room temperature and purified with reverse phasechromatography using eluent (methanol in water, from 0% to 100% v/v) togive Compound 261E.

A mixture of Compound 261E (100 mg, 0.36 mmol), Intermediate G (111 mg,0.36 mmol), and HATU (207 mg, 0.54 mmol) in DMF (5 mL) was stirred atroom temperature for 16 h. It was diluted with ethyl acetate (120 mL),washed with water (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, concentrated, and purified with prep-HPLC to yieldCompound 261. LC-MS (ESI) m/z: 573 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 0.63-0.78 (m, 4H), 1.87-2.03 (m, 4H), 3.15 (brs, 2H), 3.49-3.84(m, 4H), 4.12 (s, 4H), 4.54 (s, 1H), 4.86 (s, 1H), 6.09 (s, 1H),7.34-7.68 (m, 6H), 7.86-8.31 (m, 5H), 8.81 (s, 1H), 9.42 (s, 1H).

Example 262

To a mixture of Compound 252C (126 mg, 0.5 mmol) and Intermediate G (160mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was diluted with dichloromethane (50 mL), washed withbrine (30 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting residue was purified with reverse phasechromatography using eluent (methanol in water, from 10% to 55% v/v) tofurnish Compound 262. LC-MS (ESI) m/z: 545 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.64-0.65 (m, 2H), 0.81-0.82 (m, 2H), 1.86-2.01 (m, 4H),2.80-3.65 (m, 14H), 3.91-3.93 (m, 1H), 4.47-4.48 (m, 1H), 4.87-4.88 (m,1H), 6.04 (br s, 1H), 6.94-6.96 (m, 2H), 7.13-7.18 (m, 2H), 7.68-7.84(m, 3H), 8.69 (d, J=9.6 Hz, 1H), 10.10 (brs, 1H).

Example 263

A mixture of Compound 263A (492 mg, 2 mmol), Compound 175B (669 mg, 2.2mmol), K₂CO₃ (828 mg, 6 mmol), and Pd(dppf)Cl₂ (50 mg, 0.07 mmol) indioxane (20 mL) and water (4 mL) was stirred under nitrogen at 100° C.overnight. The solution was cooled to room temperature and adjusted topH 6 with aqueous hydrochloric acid solution (6 N, 1 mL). The solutionwas extracted with ethyl acetate (100 mL×3). The organic layer waswashed with water (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and evaporated to afford Compound 263B.

A mixture of Compound 263B (156 mg, 0.5 mmol), HATU (342 mg, 0.9 mmol),and Intermediate G (155 mg, 0.5 mmol) in dichloromethane (10 mL) and DMF(4 mL) was stirred at 25° C. overnight. The solution was extracted withethyl acetate (50 mL×2). The combined organic phases were washed withwater (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to give a residue. The crude product waspurified with prep-HPLC to afford Compound 263. LC-MS (ESI) m/z: 609[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.66-0.85 (m, 4H), 2.05-2.25(m, 4H), 3.42-3.90 (m, 7H), 4.71-4.74 (m, 1H), 5.00 (s, 1H), 7.38-7.39(m, 2H), 7.42 (s, 1H), 7.47-7.52 (m, 1H), 7.73-7.76 (m, 5H), 7.93-7.95(m, 1H), 8.08-8.09 (m, 1H).

Example 264

To a solution of Compound 247C (500 mg, 1.82 mmol) in methanol/water (10mL, 1:1, v/v) was added LiOH.H₂O (153 mg, 3.64 mmol). The reactionmixture was stirred at 15° C. for 18 h. After the reaction wascompleted, it was adjusted to pH 6 with aqueous HCl solution (3 N) andconcentrated in vacuo to give a crude compound. The crude product waslyophilized to furnish Compound 264A.

To a mixture of Compound 264A (90 mg, 0.37 mmol) in dichloromethane (5mL) was added HATU (213 mg, 0.55 mmol) and Intermediate G (115 mg, 0.37mmol). The mixture was stirred at 15° C. for 18 h. It was treated withwater (20 mL) and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were washed with water (50 mL), dried over anhydroussodium sulfate, and concentrated to give a crude compound. The crudeproduct was purified with prep-HPLC to afford Compound 264. LC-MS (ESI)m/z: 538 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.65-0.84 (m, 4H),1.87-2.08 (m, 4H), 3.10-3.26 (m, 3H), 3.62-3.72 (m, 3H), 3.91-3.95 (m,1H), 4.50-4.55 (m, 1H), 4.88 (d, J=2.8 Hz, 1H), 6.09 (brs, 1H),7.36-7.49 (m, 5H), 7.91-7.94 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 8.33 (dd,J=8.0, 2.0 Hz, 1H), 8.99 (d, J=2.0 Hz, 1H), 9.13 (d, J=9.2 Hz, 1H), 9.53(brs, 1H).

Example 265

To a solution of Compound 265A (11.6 g, 48 mmol) in1-methyl-2-pyrrolidinone (150 mL) was added cesium carbonate (33 g, 87mmol) and bromocyclopropane (16.5 mL, 1999 mmol). The mixture wasstirred for 24 h while keeping inner temperature between 145° C. and155° C. After the reaction was cooled to ambient temperature, the darksolution was diluted with water (400 mL) and extracted with a mixture ofethyl acetate in petroleum ether (15% v/v) (300 mL×3). The combinedorganic phases were washed with brine (150 mL×4), dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude productas a brown oil. The crude product was purified with flash columnchromatography on silica gel (petroleum ether) to furnish Compound 265B.

To a solution of Compound 265B (6.79 g, 8.1 mmol) in dry THF (200 mL)maintained at −70° C. was added n-BuLi (2.5 Min hexane, 9.76 mL)dropwise under nitrogen atmosphere over a period of 20 minutes. Afterthe reaction was stirred at −70° C. for 40 minutes, Intermediate A4 (3.2g, 8.1 mmol) dissolved in dry THF (20 mL) was added slowly to the coldsolution at a rate that maintained the internal temperature between −70°C. and −50° C. After the addition was complete, the solution was left tostir for 1 h. The reaction was quenched with saturated ammonium chloridesolution (400 mL) and extracted with ethyl acetate (300 mL×3). Theorganic phase was washed with water (200 mL) and brine (200 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to furnish thecrude Compound 265C. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 5%to 10% v/v) to furnish Compound 265C.

To a solution of Compound 265C (5.95 g, 110 mmol) in dry THF (70 mL) wasadded L-Selectride (1.0 Min THF, 23.7 mL) dropwise under nitrogenatmosphere while keeping the temperature at −90° C. After the additionwas complete, the solution was allowed to stir at this temperature for 1h. The reaction was quenched with saturated ammonium chloride solution(50 mL), extracted with ethyl acetate (100 mL×2), washed with water (100mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered,and concentrated to furnish a crude compound. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, 10% v/v) to give Compound 265D.

To a solution of Compound 265D (5.4 g, 10 mmol) in THF (100 mL) wasadded tetrabutylammonium fluoride (1.31 g, 5.0 mmol) at 0° C. Themixture was stirred at room temperature for 12 h. After that, thereaction mixture was evaporated to remove tetrahydrofuran. The mixturewas treated with water (50 mL) and extracted with ethyl acetate (150mL×3). The combined organic phases were washed with water (150 mL) andbrine (150 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish a crude compound. The crude product was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 20% v/v) to furnish Compound 265E.

To a solution of Compound 265E (1.18 g, 2.78 mmol) dissolved in THF (50mL) was added triethylamine (866 mg, 8.5 mmol). The mixture was cooledto −30° C., and then methanesulfonyl chloride (389 mg, 3.41 mmol) wasadded dropwise over a period of 15 minutes. After the addition wascomplete, the reaction was stirred at −30° C. for 1.5 h, diluted withwater (50 mL), and extracted with ethyl acetate (150 mL×2). The combinedorganic layers were washed with brine (150 mL), dried over anhydroussodium sulfate, filtered, and concentrated to furnish Compound 265F.

To a solution of Compound 265F (1.0 g, 1.98 mmol) in THF (30 mL) wasadded pyrrolidine (2.3 g, 32 mmol). The reaction mixture was allowed toheat to 50° C. for 16 h. The mixture was diluted with water (100 mL),extracted with ethyl acetate (150 mL×2), washed with brine (50 mL),dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish a crude compound. The crude product was purified with flashcolumn chromatography on silica gel (methanol in dichloromethane, 5%v/v) to give Compound 265G.

To a solution of Compound 265G (100 mg, 0.21 mmol) in ethanol (8 mL) andwater (2 mL) was added LiOH.H₂O (56 mg, 1.33 mmol). The mixture washeated to 80° C. and stirred for 16 h. And then it was diluted withwater (15 mL) and extracted with dichloromethane (50 mL×2). The combinedorganic phases were washed with water (50 mL) and brine (50 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to furnishCompound 265H.

A mixture of Compound 265H (100 mg, (0.21 mmol), HATU (95 mg, 0.25mmol), and Intermediate C (40.8 mg, 0.17 mmol) in DCM (15 mL) wasstirred at room temperature overnight. The reaction mixture was treatedwith water (20 mL), extracted with DCM (50 mL×2), washed with brine (50mL), dried over anhydrous sodium sulfate, and concentrated. The crudeproduct was purified with prep-HPLC to give Compound 265. LC-MS (ESI)m/z: 571.2 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.66-0.82 (m, 4H),2.04-2.23 (m, 4H), 3.23-3.26 (m, 1H), 3.60-3.89 (m, 6H), 4.72-4.76 (m,1H), 5.06 (d, J=2.4 Hz, 1H), 7.22-7.26 (m, 2H), 7.47 (d, J=8.8 Hz, 1H),7.65 (s, 1H), 7.67-7.77 (m, 8H).

Example 266

To a solution of Compound 266A (1.96 g, 10 mmol) in DMF (50 mL) wasadded sodium hydride (60% suspend in oil, 800 mg, 20 mmol) at 0° C. Themixture was stirred at 0° C. for 0.5 h and 2-iodopropane (2.55 g, 15mmol) was added at 0° C. The resultant mixture was stirred at roomtemperature overnight, diluted with ethyl acetate (100 mL), washed withwater (50 mL×3) and brine (50 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 266B.

A mixture of Compound 266B (500 mg, 2.1 mmol), Pd(dppf)Cl₂ (86 mg, 0.1mmol), 175B (638 mg, 2.1 mmol), and K₂CO₃ (668 mg, 6.3 mmol) in dioxane(15 mL) and water (2 mL) was stirred under nitrogen at 100° C.overnight. The mixture was cooled down to room temperature,concentrated, diluted with water (50 mL), and extracted with ethylacetate (30 mL×3). The aqueous layer was acidified to pH 2 with aqueousHCl solution (1 N) and extracted with dichloromethane (10 mL×3). Thedichloromethane layer was dried over anhydrous sodium sulfate andfiltered to afford Compound 266C/dichloromethane solution. A solution ofCompound 266C in dichloromethane was directly used for the next stepwithout further purification.

To a solution of Compound 266C in dichloromethane (15 mL, from previousstep) was added Intermediate G (155 mg, 0.5 mmol) and HATU (380 mg, 1mmol). The mixture was stirred at room temperature overnight. Themixture was purified with prep-HPLC to furnish Compound 266. LC-MS (ESI)m/z: 600 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.67-0.71 (m, 2H),0.81-0.86 (m, 2H), 1.48 (d, J=6.4 Hz, 6H), 1.88-1.92 (m, 2H), 2.03-2.08(m, 2H), 3.13-3.24 (m, 2H), 3.43-3.52 (m, 4H), 3.93-3.97 (m, 1H),4.56-4.61 (m, 1H), 4.79-4.86 (m, 1H), 4.89-4.89 (m, 1H), 6.04 (brs, 1H),6.56 (d, J=3.6 Hz, 1H), 7.35-7.37 (m, 1H), 7.42-7.46 (m, 2H), 7.52-7.55(m, 1H), 7.59-7.59 (m, 1H), 7.66-7.68 (m, 1H), 7.72-7.74 (m, 2H),7.78-7.80 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 8.79 (d, J=9.2 Hz, 1H), 9.34(brs, 1H).

Example 267

To a mixture of Compound 175A (2.56 g, 0.01 mol), 4-chlorophenylboronicacid (2 g, 1.32 mol), and K₃PO₄ (6.4 g, 0.03 mol) in toluene (80 mL) wasadded Pd(PPh₃)₄ (1.156 g, 0.001 mol). The reaction mixture was stirredunder nitrogen at 100° C. overnight. The resulting mixture was cooleddown to room temperature, washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered, and concentrated. The residue waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 10% to 50% v/v) to furnish Compound 267A.

To a solution of Compound 267A (2.9 g, 0.01 mol) in ethanol/water (40mL/10 mL) was added LiOH H₂O (840 mg, 0.02 mol). The mixture was stirredat room temperature for about 2 h until completion by thin layerchromatography analysis. The reaction mixture was acidified to pH 2 withaqueous HCl solution (1.0 N, 40 mL) and extracted with ethyl acetate (30mL×2). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated toafford Compound 267B.

To a mixture of Compound 267B (130 mg, 0.5 mmol) and Intermediate A (139mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith reverse phase chromatography using eluent (methanol in water, from10% to 55% v/v) to furnish Compound 267. LC-MS (ESI) m/z: 521 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.66-1.74 (m, 4H), 2.50-2.70 (m, 6H),4.21-4.22 (m, 5H), 4.75 (s, 1H), 5.57 (s, 1H), 6.82 (s, 2H), 6.87 (s,1H), 7.58-7.60 (m, 2H), 7.78-7.83 (m, 6H), 8.61 (d, J=9.6 Hz, 1H).

Example 268

To a solution of Compound 268A (3.35 g, 21.73 mmol) in methanol (10 mL)was added dropwise bromine (1.34 mL, 26.10 mmol) at −10° C. The mixturewas stirred room temperature for 5 h. It was quenched with saturatedaqueous Na₂S₂O₃ solution (100 mL) and filtered to remove the resultantsolid. The filtrate was evaporated and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 0%to 3% v/v) to afford Compound 268B.

To a solution of Compound 268B (12.00 g, 51.72 mmol) in THF (30 mL) wasadded dropwise n-BuLi (2.4 M in hexane, 22 mL, 51.72 mmol) undernitrogen at −78° C. The mixture was stirred at −78° C. for 30 min. Asolution of Intermediate A4 (6.77 g, 17.11 mmol) in THF (20 mL) wasadded dropwise under nitrogen at −78° C. The mixture was stirred at −78°C. for 20 min and quenched with saturated aqueous ammonium chloridesolution (100 mL). The mixture was diluted with ethyl acetate (300 mL),washed with water (200 mL) and brine (200 mL), dried over anhydroussodium sulfate, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to furnishCompound 268C.

To a solution of Compound 268C (7.20 g, 14.72 mmol) in THF (200 mL) wasadded dropwise L-Selectride (1 Min THF, 29 mL, 29.00 mmol) undernitrogen at −90° C. The mixture was stirred at −90° C. for 1 h andquenched with saturated aqueous ammonium chloride solution (100 mL). Itwas diluted with ethyl acetate (300 mL), washed with water (200 mL) andbrine (200 mL), dried over anhydrous sodium sulfate, and purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, from 0% to 20% v/v) to afford Compound 268D.

A mixture of Compound 268D (2.00 g, 4.07 mmol) and Bu₄NF (641 mg, 2.04mmol) in THF (20 mL) was stirred at 20° C. for 16 h. It was diluted withethyl acetate (200 mL), washed with water (200 mL) and brine (200 mL),dried over anhydrous sodium sulfate, and purified with flash columnchromatography on silica gel (methanol in dichloromethane, from 0% to 5%v/v) to give Compound 268E.

To a solution of Compound 268E (1.70 g, 4.50 mmol) and triethylamine(909 mg, 9.00 mmol) in THF (20 mL) was added dropwise methanesulfonylchloride (565 mg, 4.96 mmol) at −15° C. The mixture was stirred at −15°C. for 1 h. It was quenched with saturated ice water (50 mL), dilutedwith ethyl acetate (200 mL), washed with water (150 mL) and brine (200mL), dried over anhydrous sodium sulfate, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 0%to 80% v/v) to afford Compound 268F.

A solution of Compound 268F (1.50 g, 3.30 mmol) and pyrrolidine (2.34 g,32.92 mmol) in THF (10 mL) was stirred at 50° C. for 16 h. It wasdiluted with ethyl acetate (200 mL), washed with water (200 mL) andbrine (200 mL), dried over anhydrous sodium sulfate, and purified withreverse phase chromatography using eluent (methanol in water, from 0% to100% v/v) to furnish Compound 268G.

A mixture of Compound 268G (900 mg, 2.09 mmol) and Pd(OH)₂/C (20%, 500mg) in methanol (10 mL) was stirred under hydrogen at 20° C. for 16 h.It was filtered to remove Pd(OH)₂/C and the filtrate was evaporated togive Compound 268H.

A mixture of Compound 268H (100 mg, 0.34 mmol), Compound 133D (82 mg,0.34 mmol), and HATU (194 mg, 0.51 mmol) in DMF (5 mL) was stirred atroom temperature for 16 h. It was diluted with ethyl acetate (120 mL),washed with water (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, concentrated, and purified with prep-HPLC to yieldCompound 268. LC-MS (ESI) m/z: 523 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.82-2.03 (m, 4H), 3.08-3.19 (m, 2H), 3.47-3.60 (m, 4H), 4.17-4.30(m, 4H), 4.4-4.54 (m, 1H), 4.80 (d, J=8.0 Hz, 1H), 6.10 (s, 1H), 6.75(d, J=7.6 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 7.37 (t, J=8.8 Hz, 2H),7.79-7.90 (m, 6H), 9.01 (d, J=8.8 Hz, 1H), 9.41 (s, 1H).

Example 269

To a solution of Compound 266C in dichloromethane (15 mL, from previousstep) was added Intermediate C (150 mg, 0.5 mmol) and HATU (380 mg, 1mmol). The mixture was stirred at room temperature overnight. Themixture was directly purified with prep-HPLC to afford Compound 269.LC-MS (ESI) m/z: 586 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.48 (d,J=6.8 Hz, 6H), 1.88-1.89 (m, 2H), 2.03-2.03 (m, 2H), 3.12-3.20 (m, 2H),3.45-3.55 (m, 4H), 4.28-4.30 (m, 4H), 4.51-4.54 (m, 1H), 4.79-4.83 (m,2H), 6.04-6.05 (m, 1H), 6.57-6.58 (m, 1H), 6.78 (s, 1H), 6.83-6.85 (m,1H), 7.53-7.55 (m, 1H), 7.58-7.59 (m, 1H), 7.65-7.67 (m, 1H), 7.83-7.89(m, 4H), 7.96-7.97 (m, 1H), 8.73-8.76 (m, 1H), 9.36 (brs, 1H).

Example 270

To a mixture of Compound 266C (130 mg, 0.5 mmol) and Intermediate G (151mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith reverse phase chromatography using eluent (methanol in water, from10% to 55% v/v) to furnish Compound 270. LC-MS (ESI) m/z: 553 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.66-0.83 (m, 4H), 1.88-2.04 (m, 4H),3.15-3.20 (m, 2H), 3.49-3.56 (m, 4H), 3.93 (s, 1H), 4.56 (s, 1H), 4.88(s, 1H), 6.07 (s, 1H), 7.36-7.44 (m, 3H), 7.59-7.62 (m, 2H), 7.77-7.80(m, 6H), 8.80-8.83 (d, J=10.0 Hz, 1H), 9.48 (s, 1H).

Example 271

To a solution of Compound 271A (6.6 g, 30 mmol) in dichloromethane (30mL) was added propan-2-amine (3.54 g, 60 mmol) at 0° C. The mixture wasstirred at 40° C. overnight and the mixture was dispersed between water(100 mL) and ethyl acetate (200 mL). After separation, the organic phasewas washed with water (10 mL×3) and brine (10 mL), dried over anhydroussodium sulfate, filtered, and concentrated to afford the Compound 271B.

To a solution of Compound 271B (2.0 g, 7.75 mmol) in ethanol (60 mL) wasadded stannic chloride (5.25 g, 23.3 mmol). The mixture was stirred atreflux for 4 h. After cooling down to room temperature, aqueous sodiumhydroxide solution (4 N, 5 mL) was added dropwise to the mixture and theresulting mixture was filtered. After removal of solvent, the residuewas extracted with ethyl acetate (50 mL×3), washed with water (10 mL×2)and brine (10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 0%to 20% v/v) to furnish Compound 271C.

To a solution of Compound 271C (1.3 g, 5.70 mmol) in DMF (30 mL) wasadded triethoxymethane (4.74 mL, 28.5 mmol) and con. HCl (1.5 mL). Themixture was stirred at 100° C. for 8 h. After cooling down to roomtemperature, the mixture was poured into water (150 mL) and adjusted topH 8 with saturated aqueous sodium bicarbonate solution (3.5 mL). Themixture was extracted with ethyl acetate (50 mL×3) and separated. Thecombined organic phases were washed with water (10 mL×2) and brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated.The crude product was purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, from 0% to 50% v/v) toyield Compound 271D.

To a solution of Compound 271D (476 mg, 2.0 mmol) in dioxane (30 mL) andwater (5 mL) was added K₂CO₃ (828 mg, 6.0 mmol), Compound 175B (608 mg,2.0 mmol), and Pd(dppf)Cl₂ (146 mg, 0.2 mmol). The mixture was stirredunder nitrogen at 100° C. for 2 h. After removal of solvent, the residuewas dissolved in ethyl acetate (150 mL), washed with water (5 mL×2) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to yield a crude compound. The crude product was purifiedwith reverse phase chromatography using eluent (methanol in pure water,50% v/v) to give Compound 271E.

To a solution of Intermediate G (121 mg, 0.39 mmol) in DMF (10 mL) wasadded Compound 271E (100 mg, 0.32 mmol), HATU (182 mg, 0.48 mmol), andN,N-diisopropylethylamine (124 mg, 0.96 mmol). The mixture was stirredunder nitrogen at 25° C. overnight. The resulting mixture was quenchedwith saturated aqueous sodium bicarbonate solution (5 mL) and extractedwith ethyl acetate (50 mL×3). The combined organic phases were washedwith water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford a crude compound. The crude productwas purified with prep-HPLC to furnish Compound 271. LC-MS (ESI) m/z:601 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.68-0.70 (m, 2H),0.82-0.83 (m, 2H), 1.65 (d, J=6.4 Hz, 6H), 1.90-1.93 (m, 2H), 2.02-2.05(m, 2H), 3.14-3.24 (m, 2H), 3.50-3.59 (m, 4H), 3.93-3.97 (m, 1H),4.57-4.60 (m, 1H), 4.92 (d, J=2.4 Hz, 1H), 5.02-5.09 (m, 1H), 7.36-7.46(m, 3H), 7.81-7.88 (m, 4H), 7.92-7.95 (m, 1H), 8.16-8.19 (m, 2H), 9.54(s, 1H), 9.84 (brs, 1H).

Example 272

To a mixture of Compound 267B (130 mg, 0.5 mmol) and Intermediate C (143mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith reverse phase chromatography using eluent (methanol in water, from10% to 55% v/v) to furnish Compound 272. LC-MS (ESI) m/z: 539 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.87-2.03 (m, 4H), 3.10-3.18 (m, 2H),3.42-3.54 (m, 4H), 4.23-4.28 (m, 4H), 4.51 (s, 1H), 4.78 (s, 1H), 6.05(s, 1H), 6.76 (s, 1H), 6.81 (d, J=11.6 Hz, 1H), 7.59 (m, 2H), 7.79-7.84(m, 4H), 7.91-7.93 (m, 2H), 8.75 (d, J=10.0 Hz, 1H), 9.37 (s, 1H).

Example 273

A mixture of 4-bromoaniline (2 g, 11.7 mmol), Cs₂CO₃ (11.4 g, 35.1mmol), and 1, 4-dibromobutane (3.7 g, 17.5 mmol) in DMF (40 mL) wasstirred under nitrogen at 60° C. for 16 h. The mixture was cooled toroom temperature, diluted with ethyl acetate (200 mL), washed with water(50 mL×2) and brine (50 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to affordCompound 273A.

To a solution of Compound 273A (300 mg, 1.3 mmol) in dry THF (10 mL) wasadded n-BuLi (2.5 N in hexane, 0.6 mL, 1.5 mmol) under nitrogen at −78°C. The resulting solution was stirred at −78° C. for 30 min andtransferred into a stirred solution of diethyl oxalate (0.97 g, 6.6mmol) in dry THF (5 mL) at this temperature. The solution was stirred at−78° C. for 1 h, quenched with addition of saturated aqueous ammoniumchloride solution (10 mL), poured into water (50 mL), and extracted withethyl acetate (50 mL×2). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated invacuo to give Compound 273B.

A mixture of Compound 273B (0.2 g, 0.8 mmol) and LiOH.H₂O (68 mg, 1.6mmol) in THF (5 mL) and water (2 mL) was stirred at 0° C. for 2 h. Themixture was diluted with ethyl acetate (30 mL), washed with water (10mL×2) and brine (10 mL), dried over anhydrous sodium sulfate,concentrated, and purified with reverse phase chromatography usingeluent (methanol in water, from 0% to 100% v/v) to afford Compound 273C.

A mixture of Compound 273C (74 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol),and Intermediate C (100 mg, 0.3 mmol) in dichloromethane (5 mL) wasstirred at 25° C. for 16 h. The mixture was diluted with ethyl acetate(30 mL), washed with water (10 mL×2) and brine (10 mL), dried overanhydrous sodium sulfate, concentrated, and purified with prep-HPLC tofurnish Compound 273. LC-MS (ESI) m/z: 498 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 1.85 (s, 2H), 1.98 (s, 6H), 3.09-3.17 (m, 2H), 3.41-3.53(m, 4H), 3.98-4.11 (m, 4H), 4.27 (m, 4H), 4.47 (s, 1H), 4.74 (s, 1H),6.55 (d, J=9.2 Hz, 2H), 6.72-6.81 (m, 2H), 7.75 (d, J=8.8 Hz, 2H), 8.42(d, J=9.6 Hz, 1H), 9.28 (s, 1H).

Example 274

A mixture of (4-(trifluoromethyl)phenyl)boronic acid (500 mg, 2.63mmol), Compound 175A (615 mg, 2.39 mmol), Pd(dppf)Cl₂ (87.5 mg, 0.12mmol), potassium carbonate (992 mg, 7.18 mmol), water (3 mL), and1,4-dioxane (10 mL) was heated under nitrogen atmosphere at 90° C. for 2h. After cooling, water (5 mL) was added, and the mixture was extractedwith ethyl acetate (20 mL×3). The combined organic layers were washeduntil neutralization and dried over anhydrous sodium sulfate. Afterremoval of the solvent in vacuo, the crude product was purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, from 10% to 20% v/v) to furnish Compound 274A.

A mixture of Compound 274A (130 mg, 0.44 mmol), Intermediate G (164 mg,0.53 mmol), and HATU (252 mg, 0.66 mmol) in dichloromethane (10 mL) wasstirred under nitrogen atmosphere at 25° C. for 5 h. The mixture wasquenched with water (5 mL). The organic layer was washed with brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated invacuo to afford a crude compound. The crude product was purified withprep-HPLC to furnish Compound 274. LC-MS (ESI) m/z: 587 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.64-0.68 (m, 2H), 0.79-0.84 (m, 2H),1.88-1.91 (m, 2H), 1.99-2.04 (m, 2H), 3.14-3.19 (m, 2H), 3.47-3.49 (m,3H), 3.87-3.95 (m, 1H), 4.55 (t, J=4.0 Hz, 1H), 4.87 (s, 1H), 6.05 (d,J=4.0 Hz, 1H), 7.33-7.44 (m, 3H), 7.85-7.89 (m, 4H), 7.91-7.99 (m, 4H),8.82 (d, J=9.7 Hz, 1H), 9.34 (brs, 1H).

Example 275

To a suspension of 5-bromo-1H-indazole (600 mg, 3.1 mmol) in1,2-dichloroethane (30 mL) was added cyclopropylboronic acid (532 mg,6.2 mmol), copper acetate (562 mg, 6.2 mmol), sodium carbonate (658 mg,6.2 mmol), 2,2′-bipyridine (967 mg, 6.2 mmol) and molecular sieve (2.0g) at room temperature. The reaction mixture was stirred at roomtemperature for 48 h. The reaction was quenched with saturated aqueousammonium chloride solution and extracted with dichloromethane (50 mL×2).The combined organic extracts were washed with brine (100 mL×2) anddried over anhydrous sodium sulfate. After filtration, the solvent wasremoved in vacuo and the residue was purified with prep-TLC (ethylacetate in petroleum ether, 10% v/v) to give Compound 275A.

To a solution of Compound 275A (575 mg, 2.43 mmol) in 1,4-dioxane (15mL) was added 175B (738 mg, 2.43 mmol), Pd(dppf)Cl₂ (98 mg, 0.12 mmol),potassium carbonate (1.06 g, 7.29 mmol) and water (1 mL) under nitrogen.The reaction mixture was stirred at 110° C. for 3 hours. The resultingmixture was cooled to 25° C. The precipitated solid was filtered anddried to afford Compound 275B.

To a solution of Compound 275B (60 mg, 0.196 mmol) in DMF (5 mL) wasadded Intermediate C (58 mg, 0.196 mmol) and HATU (111 mg, 0.294 mmol).The reaction mixture was stirred at 20° C. for 2 h. The mixture waspurified with prep-HPLC to yield the product Compound 275. LC-MS (m/z)585 [M+H]⁺; ¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 1.27-1.29 (m, 4H),2.06-2.13 (m, 2H), 2.28-2.30 (m, 2H), 3.50-3.63 (m, 2H), 4.04-4.11 (m,5H), 4.23-4.31 (m, 5H), 4.90-4.91 (m, 1H), 5.10-5.11 (m, 1H), 6.82-6.88(m, 2H), 7.87-7.95 (m, 4H), 8.11-8.14 (m, 3H), 8.24-8.25 (m, 1H), 8.35(s, 1H).

Example 276

A mixture of Intermediate D (97 mg, 0.31 mmol), Compound 275B (80 mg,0.26 mmol), and HATU (150 mg, 0.40 mmol) in DMF (5 mL) was stirred at10° C. for 1.5 h. And then it was purified with prep-HPLC to yieldCompound 276. LC-MS (ESI) m/z: 601 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ(ppm) 1.18-1.19 (m, 4H), 2.03-2.17 (m, 2H), 2.24 (s, 2H), 3.47 (m, 3H),3.73-3.83 (m, 2H), 3.88-3.99 (m, 3H), 4.20-4.38 (m, 4H), 4.87 (s, 1H),5.14 (d, J=2.0 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H),7.83 (d, J=8.4 Hz, 4H), 8.03 (d, J=9.6 Hz, 3H), 8.15 (d, J=10.4 Hz, 2H),9.93 (brs, 1H).

Example 277

To a solution of Compound 275B (60 mg, 0.196 mmol) in DMF (5 mL) wasadded Intermediate G (60 mg, 0.196 mmol) and HATU (111 mg, 0.294 mmol).The reaction mixture was stirred at 20° C. for 2 h. The mixture waspurified with prep-HPLC to yield Compound 277. LC-MS (m/z) 599 [M+H]⁺;¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 0.69-0.71 (m, 2H), 0.79-0.84 (m,2H), 1.18-1.20 (m, 4H), 2.06-2.09 (m, 1H), 2.25-2.27 (m, 2H), 3.46-3.55(m, 2H), 3.77-3.78 (m, 1H), 3.88-3.92 (m, 2H), 3.96-4.08 (m, 4H),4.90-4.94 (m, 1H), 5.20 (s, 1H), 7.36-7.46 (m, 2H), 7.51-7.52 (m, 1H),7.80-7.82 (m, 4H), 7.98-8.00 (m, 2H), 8.05 (s, 1H), 8.14 (s, 1H),8.17-8.20 (m, 1H), 9.14 (brs, 1H).

Example 278

To a solution of Compound 275B (60 mg, 0.196 mmol) in DMF (5 mL) wasadded Intermediate H (55 mg, 0.196 mmol) and HATU (111 mg, 0.294 mmol).The reaction mixture was stirred at 20° C. for 2 h. The mixture waspurified with prep-HPLC to yield Compound 278. LC-MS (ESI) m/z: 571[M+H]⁺; ¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 1.33-1.37 (m, 4H),2.60-2.62 (m, 1H), 2.71-2.74 (m, 1H), 3.92-3.95 (m, 3H), 4.27-4.31 (m,4H), 4.61-4.64 (m, 4H), 4.73-4.74 (m, 1H), 5.10-5.11 (m, 1H), 6.82-6.88(m, 2H), 7.88-7.90 (m, 2H), 7.98-8.10 (m, 4H), 8.31 (s, 1H), 8.56 (s,1H).

Example 279

To a solution of Compound 205A (70 mg, 0.25 mmol) in DMF (3 mL) wasadded Intermediate I (74 mg, 0.25 mmol) and HATU (142 mg, 0.375 mmol).The reaction mixture was stirred at 15° C. overnight. The mixture waspurified with prep-HPLC to yield Compound 279. LC-MS (m/z) 559 [M+H]⁺;¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 0.70-0.73 (m, 2H), 0.80-0.84 (m,2H), 2.56-2.57 (m, 1H), 2.71-2.74 (m, 1H), 3.86-3.96 (m, 4H), 4.13 (s,3H), 4.47-4.60 (m, 4H), 4.77-4.78 (m, 1H), 5.20-5.21 (m, 1H), 7.39-7.45(m, 2H), 7.50-7.51 (m, 1H), 7.71-7.74 (m, 1H), 7.79-7.82 (m, 3H),7.93-7.95 (m, 2H), 8.09 (s, 1H), 8.13-8.15 (m, 2H), 9.51 (brs, 1H).

Example 280

A mixture of Compound 280A (2 g, 10 mmol), hydroxylamine hydrochloride(830 mg, 12 mmol), and sodium acetate (656 mg, 8 mmol) in water (5 mL)and ethanol (20 mL) was stirred under nitrogen at 25° C. for 5 h. Thesolution was concentrated to dryness. The crude product was washed withwater (5 mL) and dried to afford Compound 280B.

To a solution of Compound 280B (717 mg, 3.3 mmol) in DMSO (10 mL) wasadded potassium carbonate (638 mg, 4.6 mmol) at 25° C. The mixture wasstirred at 120° C. overnight. The solution was cooled to roomtemperature and extracted with ethyl acetate (100 mL×2). The combinedorganic layers were washed with water (50 mL) and brine (50 mL), driedover anhydrous sodium sulfate, filtered, and evaporated to give Compound280C.

A mixture of Compound 280C (197 mg, 1 mmol), Compound 175B (334 mg, 1.1mmol), potassium carbonate (414 mg, 3 mmol), and Pd(dppf)Cl₂ (20 mg,0.04 mmol) in dioxane (10 mL) and water (2 mL) was stirred undernitrogen at 100° C. overnight. The solution was cooled to roomtemperature, adjusted to pH 4 with aqueous hydrochloric acid solution (6N, 2 mL), and extracted with ethyl acetate (100 mL×3). The organic layerwas washed with water (50 mL) and brine (50 mL), dried over anhydroussodium sulfate, filtered, and evaporated to afford Compound 280D.

A mixture of Compound 280D (133.5 mg, 0.5 mmol), HATU (342 mg, 0.9mmol), and Intermediate C (148 mg, 0.5 mmol) in dichloromethane (10 mL)and DMF (4 mL) was stirred at 25° C. overnight. The solution wasextracted with ethyl acetate (50 mL×2). The combined organic phases werewashed with water (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to give a residue. The residue waspurified with prep-HPLC to furnish Compound 280. LC-MS (ESI) m/z: 546[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.84-2.03 (m, 4H), 3.09-3.20(m, 2H), 3.45-3.53 (m, 4H), 4.22-4.32 (m, 4H), 4.47-4.50 (m, 1H), 4.77(s, 1H), 6.04 (s, 1H), 6.76-6.84 (m, 2H), 7.29-7.32 (m, 2H), 7.76-7.79(m, 3H), 7.92-7.94 (m, 2H), 8.76-8.79 (m, 1H), 9.24-9.26 (m, 1H), 11.41(s, 1H).

Example 281

Solvent 1,2-dichloroethane (30 mL) was added to a 500 mL ofround-bottomed flask containing 6-bromoindazole (3 g, 15.2 mmol),cyclopropylboronic acid (2.6 g, 30.4 mmol), Cu(OAc)₂ (5.5 g, 30.4 mmol),Na₂CO₃ (3.2 g, 30.4 mmol), bipyridine (1.7 g, 30.4 mmol), and 4 Åmolecular sieve (8 g). The flask was equipped with a drying tube. Themixture was stirred at room temperature for 4 days and filtered throughcelite. The filtrate was diluted with water (200 mL) and extracted withethyl acetate (100 mL×3). The combined organic layers were washed withbrine (200 mL), dried over anhydrous sodium sulfate, and concentrated.The residue was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 0% to 10% v/v) to give Compound281A and Compound 281B.

A mixture of Compound 281A (600 mg, 2.53 mmol), Compound 175B (769 mg,2.53 mmol), Pd(dppf)Cl₂ (106 mg, 0.13 mmol), and K₂CO₃ (1.05 g, 7.59mmol) in dioxane (10 mL) and water (10 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was diluted with water (100 mL)and extracted with ethyl acetate (100 mL×2). The organic layers werediscarded off. The aqueous layer was acidified to pH 3 with aqueous HClsolution (1 N) and extracted with ethyl acetate (100 mL×2). The combinedorganic layers were washed with water (100 mL×2) and brine (100 mL),dried over anhydrous sodium sulfate, and concentrated to give Compound281C.

A mixture of Compound 281C (100 mg, 0.33 mmol), HATU (190 mg, 0.50mmol), and Intermediate G (102 mg, 0.33 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was directly purified with prep-HPLC tofurnish Compound 281. LC-MS (ESI) m/z: 599 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.66-0.85 (m, 4H), 1.17-1.19 (m, 4H), 1.88-2.08 (m, 4H),3.12-3.25 (m, 2H), 3.48-3.59 (m, 4H), 3.83-3.88 (m, 1H), 3.93-3.98 (m,1H), 4.56-4.63 (m, 1H), 4.90 (s, 1H), 6.17 (brs, 1H), 7.37 (dd, J=8.8,2.4 Hz, 1H), 7.43-7.47 (m, 2H), 7.55 (dd, J=8.4, 1.2 Hz, 1H), 7.79 (d,J=8.0 Hz, 2H), 7.88-7.92 (m, 3H), 8.03 (s, 1H), 8.09 (s, 1H), 8.86 (d,J=10.0 Hz, 1H), 9.41 (brs, 1H).

Example 282

A mixture of Compound 281C (100 mg, 0.33 mmol), HATU (190 mg, 0.50mmol), and Intermediate C (98 mg, 0.33 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was directly purified with prep-HPLC tofurnish Compound 282. LC-MS (ESI) m/z: 585 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 1.17-1.19 (m, 4H), 1.88-2.08 (m, 4H), 3.11-3.22 (m, 2H),3.46-3.56 (m, 4H), 3.84-3.89 (m, 1H), 4.29-4.31 (m, 4H), 4.52-4.54 (m,1H), 4.80 (d, J=2.4 Hz, 1H), 6.05 (brs, 1H), 6.79 (s, 1H), 6.84 (d,J=12.0 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.89-7.94 (m, 5H), 8.04 (s, 1H),8.09 (s, 1H), 8.79 (d, J=9.2 Hz, 1H), 9.33 (brs, 1H).

Example 283

A mixture of Compound 281C (100 mg, 0.33 mmol), HATU (190 mg, 0.50mmol), and Intermediate H (93 mg, 0.33 mmol) in DMF (5 mL) was stirredat 10° C. for 18 h. The mixture was directly purified with prep-HPLC tofurnish Compound 283. LC-MS (ESI) m/z: 571 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 1.16-1.18 (m, 4H), 2.26-2.30 (m, 1H), 2.40-2.48 (m, 1H),3.32-3.39 (m, 1H), 3.49-3.54 (m, 1H), 3.84-3.89 (m, 1H), 4.05-4.40 (m,9H), 4.76 (d, J=3.2 Hz, 1H), 6.03 (brs, 1H), 6.78 (s, 1H), 6.83 (dd,J=11.2, 1.6 Hz, 1H), 7.55 (dd, J=8.4, 1.2 Hz, 1H), 7.85-7.94 (m, 5H),8.03 (s, 1H), 8.09 (s, 1H), 8.79 (d, J=9.6 Hz, 1H), 9.65 (brs, 1H).

Example 284

A mixture of Compound 281B (100 mg, 0.42 mmol), Compound 175B (128 mg,0.42 mmol), Pd(dppf)Cl₂ (17 mg, 0.02 mmol), and K₂CO₃ (174 mg, 1.26mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was diluted with water (100 mL),extracted with ethyl acetate (100 mL×2), and the organic layer wasdiscarded off. The aqueous layer was acidified to pH 3 with aqueous HClsolution (1 N) and extracted with ethyl acetate (100 mL×2). The combinedorganic layers were washed with water (100 mL×2) and brine (100 mL),dried over anhydrous sodium sulfate, and concentrated to give Compound284A.

A mixture of Compound 284A (80 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol),and Intermediate G (81 mg, 0.26 mmol) in DMF (5 mL) was stirred at 10°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 284. LC-MS (ESI) m/z: 599 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 0.67-0.85 (m, 4H), 1.12-1.34 (m, 4H), 1.87-1.92 (m, 4H), 3.11-3.24(m, 2H), 3.46-3.58 (m, 4H), 3.92-3.96 (m, 1H), 4.18-4.23 (m, 1H),4.43-4.56 (m, 1H), 4.89 (d, J=2.8 Hz, 1H), 6.05 (brs, 1H), 7.35-7.46 (m,4H), 7.77 (d, J=8.4 Hz, 2H), 7.81-7.85 (m, 3H), 7.97 (s, 1H), 8.55 (s,1H), 8.83 (d, J=10.0 Hz, 1H), 9.38 (brs, 1H).

Example 285

A mixture of Intermediate W (89 mg, 0.30 mmol), Compound 281C (90 mg,0.30 mmol), and HATU (148 mg, 0.39 mmol) in DMF (4 mL) was stirred at10° C. for 1.5 h. And then it was purified with prep-HPLC to yieldCompound 285. LC-MS (ESI) m/z: 587 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ(ppm) 1.21-1.23 (m, 4H), 2.56-2.65 (m, 1H), 2.69-2.81 (m, 1H), 3.77-3.82(m, 1H), 3.91-4.05 (m, 2H), 4.21-4.39 (m, 4H), 4.50-4.68 (m, 4H),4.72-4.78 (m, 1H), 5.11 (d, J=2.8 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 7.08(d, J=2.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 4H), 8.02 (t, J=8.4 Hz, 2H), 8.10(d, J=9.6 Hz, 1H), 8.14 (s, 1H), 8.18 (s, 1H), 8.86 (brs, 1H).

Example 286

To a solution of Compound 286A (5 g, 31 mmol) in 2,2,2-trifluoroaceticacid (50 mL) was added hexamethylenetramine (4.7 g, 33.6 mmol). Thereaction solution was heated at reflux overnight. After cooling, themixture was treated with 50% H₂SO₄ (20 mL) at room temperature for 4 hand extracted with ether (50 mL×3). The combined ether phases werewashed with aqueous HCl solution (5 M, 50 mL), water (50 mL) and brine(50 mL), dried over anhydrous sodium sulfate, concentrated, and purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 10% v/v) to afford Compound 286B.

To a solution of Compound 286B (1 g, 5.3 mmol) in acetonitrile (15 mL)was added NBS (0.88 g, 5.3 mmol) and ammonium formate (32 mg, 0.5 mmol)at 0° C. The mixture was stirred at room temperature for 2 h. Thesolvent was removed to give yellow solid. The yellow solid was dilutedwith ethyl acetate (100 mL), washed with brine (100 mL), dried overanhydrous sodium sulfate, and concentrated to yield Compound 286C.

To a solution of Compound 286C (1.3 g, 4.8 mmol) in THF (10 mL) wasadded dropwise aqueous NaOH solution (0.05 N, 18 mL) at 0° C., and 30%H₂O₂ (2.3 mL) was added dropwise. The mixture was stirred at roomtemperature for 2 h. Other portion of 30% H₂O₂ (2.3 mL) was addeddropwise. The mixture was stirred for 4 h. It was cooled to 0° C. andaq. NaOH solution (2 N, 2 mL) was added dropwise until pH 10-11. Themixture was stirred at 25° C. for 0.5 h, adjusted to pH 2˜3 withconcentrated HCl at 0° C., and extracted with dichloromethane (20 mL×3).The organic layers were washed with brine (20 mL×2), dried overanhydrous sodium sulfate, and concentrated to give Compound 286D.

To a mixture of Compound 286D (1.2 g, 4.7 mol) and K₂CO₃ (1.9 g, 14.1mol) in DMF (12 mL) was added 1, 2-dibromoethane (4.4 g, 23.5 mol). Themixture was stirred at 80° C. for 4 h. It was cooled down to roomtemperature and filtered. The cake was washed with ethyl acetate (50mL). The filtrate was diluted with water (50 mL) and extracted withethyl acetate (50 mL×3). The organic layer was washed with water (50mL×5) and brine (50 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum, 5% v/v) to furnish Compound 286E.

To a solution of Compound 286E (0.9 g, 3.2 mmol) in dry THF (10 mL) wasadded n-BuLi solution (2.5 N in hexane, 1.3 mL) under nitrogen at −60°C. The above mixture was stirred at −60° C. for 0.5 h. A solution ofCompound A4 (0.4 g, 1.1 mmol) in THF (4 mL) was added. The resultingmixture was stirred at −60° C. for 0.5 h, quenched with saturatedaqueous ammonium chloride solution (20 mL), extracted with ethyl acetate(30 mL×2), washed with brine (30 mL), dried over anhydrous sodiumsulfate, and concentrated to give a crude compound. The crude productwas purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 10% v/v) to yield Compound 286F.

To a solution of Compound 286F (4.8 g, 8.9 mmol) in THF (25 mL) andwater (25 mL) was added acetic acid (75 mL). The resulting mixture wasstirred at 35° C. for 16 h, diluted with brine (150 mL), and adjusted topH 8 with saturated aqueous sodium bicarbonate solution (75 mL). Themixture was extracted with ethyl acetate (100 mL×2), washed with brine(100 mL), dried over anhydrous sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (ethyl acetatein petroleum, 20% v/v) to afford Compound 286G.

To a solution of Compound 286G (2 g, 4.7 mmol) in dry THF (60 mL) wasadded dropwise DIBAL-H (1 N in toluene, 9.4 mL, 9.4 mmol) under nitrogenat −80° C. The resultant mixture was stirred at −80° C. for 30 min andadditional DIBAL-H (1 N in toluene, 9.4 mL, 9.4 mmol) was added dropwiseagain. The mixture was stirred at −80° C. for 1 h and quenched withaqueous HCl solution (2 N, 28 mL) at −20° C. The mixture was extractedwith ethyl acetate (200 mL×2), washed with water (200 mL) and brine (100mL), dried over anhydrous sodium sulfate, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum, 50% v/v) tofurnish Compound 286H.

To a solution of Compound 286H (1.5 g, 3.5 mmol) in THF (50 mL) wasadded triethylamine (1.1 g, 10.5 mmol). The mixture was cooled to −20°C. and MsCl (0.44 g, 3.9 mmol) was added slowly. The mixture was stirredat −20° C. for about half an hour and pyrrolidine (2.1 g, 30 mmol) wasadded to the mixture. The resulting mixture was stirred at −60° C. for16 h and cooled to 25° C. The mixture was diluted with ethyl acetate(200 mL), washed with water (50 mL×2) and brine (50 mL), dried overanhydrous sodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (methanol in dichloromethane, from 5% to10% v/v) to give Compound 2861.

To a solution of Compound 2861 (0.5 g, 1.2 mmol) in methanol (10 mL) wasadded Pd(OH)₂ (100 mg). The mixture was stirred under hydrogen at roomtemperature overnight. After removal of Pd(OH)₂ by filtration, thefiltrate was evaporated to furnish Compound 286J.

A mixture of Compound 2861 (0.1 g, 0.28 mmol), HATU (0.16 g, 0.43 mmol),and Intermediate C (70 mg, 0.28 mmol) in DMF (3 mL) was stirred at 25°C. for 16 h. The mixture was diluted with ethyl acetate (30 mL), washedwith water (10 mL×2) and brine (10 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with prep-HPLC to yield Compound286. LC-MS (ESI) m/z: 573 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)1.88-1.89 (m, 2H), 2.03-2.04 (m, 2H), 3.14-3.20 (m, 2H), 3.52-3.55 (m,4H), 4.29-4.35 (m, 4H), 4.53-4.56 (m, 1H), 4.87 (s, 1H), 6.10 (d, J=4Hz, 1H), 7.20-7.23 (m, 2H), 7.35-7.40 (m, 2H), 7.79-7.88 (m, 6H),8.77-8.79 (m, 1H), 9.30 (s, 1H).

Example 287

A mixture of Compound 264A (100 mg, 0.40 mmol), Intermediate G (150 mg,0.48 mmol), and HATU (233 mg, 0.60 mmol) in dichloromethane (2 mL) andDMF (2 mL) was stirred at 25° C. for 15 h. After the reaction wascompleted, it was poured into water (20 mL) and extracted withdichloromethane (20 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, concentrated in vacuo, and purified withprep-HPLC to afford Compound 287. LC-MS (ESI) m/z: 538 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.68-0.81 (m, 4H), 1.88-2.04 (m, 5H),3.01-3.20 (m, 3H), 3.41-3.55 (m, 4H), 4.51-4.53 (m, 1H), 4.86 (s, 1H),7.32-7.44 (m, 5H), 8.12-8.31 (m, 4H), 8.76-8.81 (m, 1H), 9.01 (s, 1H).

Example 288

A mixture of 5-bromoindazole (4 g, 20.3 mmol), 4-methylbenzenesulfonicacid (1.9 g, 10.1 mmol), and DHP (3.4 g, 40.6 mmol) in dichloromethane(50 mL) was stirred at room temperature for 18 hours. The reactionmixture was treated with ethyl acetate (500 mL), washed with sodiumbicarbonate solution (500 mL×3) and water (500 mL×3), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 10% to 33% v/v) to furnish Compound 288A.

To a solution of Compound 288A (4.2 g, 14.8 mmol) in dry THF (50 mL) wasadded dropwise n-BuLi (2.0 M, 7.5 mL, 17.8 mmol) under nitrogen at −70°C. After stirring for 30 min., diethyl oxalate (6.5 g, 44.4 mmol) wasadded quickly. The mixture was stirred at −70° C. for one hour. It wasquenched with saturated ammonium chloride solution (10 mL) and extractedwith ethyl acetate (50 mL×3). The combined organic phases were washedwith water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to give a residue. The residue was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, from 0% to 20% v/v) to afford Compound 288B.

To a solution of Compound 288B (1.4 g, 4.6 mmol) in ethanol (10 mL) wasadded dropwise 2 N hydrogen chloride (10 mL, 18.5 mmol). The reactionmixture was stirred at room temperature for 8 h. Sodium bicarbonatesolution was added to adjust pH 7, followed by extraction with ethylacetate (50 mL×3). The combined organic phases were washed with water (5mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish Compound 288C.

A mixture of Compound 288C (500 mg, 2.29 mmol),1-(bromomethyl)-4-fluorobenzene (647 mg, 3.44 mmol), and Cs₂CO₃ (897 mg,2.75 mmol) in 1-methylpyrrolidin-2-one (20 mL) was stirred at roomtemperature for 18 hours. The reaction mixture was treated with H₂O (50mL) and ethyl acetate (50 mL), washed with and water (500 mL×3), driedover anhydrous sodium sulfate, and concentrated. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 10% to 33% v/v) to furnish Compound 288D andCompound 288E.

To a solution of Compound 288D (300 mg, 0.91 mmol) in THF (2 mL) wasadded dropwise 1 N lithium hydroxide (2 mL, 2 mmol). The reactionmixture was stirred at room temperature for 2 h. After the reactionmixture was concentrated, 2 N HCl (1 mL) was added to adjust pH 7, andextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed with water (5 mL) and brine (5 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to furnish Compound 288F.

To a solution of Compound 288F (50 mg, 0.167 mmol) in dichloromethane (3mL) was added Intermediate G (62 mg, 0.201 mmol) and HATU (95 mg, 0.25mmol). The mixture was stirred at room temperature for 2 h. It wasconcentrated and the resulting residue was purified with prep-HPLC toafford Compound 288. LC-MS (ESI) m/z: 591 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 0.68-0.91 (m, 4H), 2.11-2.15 (m, 4H), 2.97-3.05 (m, 2H),3.48-3.50 (m, 1H), 3.65-3.68 (m, 1H), 3.70-3.85 (m, 1H), 3.87-3.91 (m,2H), 4.53-4.57 (m, 1H), 5.01-5.06 (m, 1H), 5.56 (s, 2H), 6.96-7.00 (m,2H), 7.13-7.19 (m, 3H), 7.20-7.23 (m, 1H), 7.28-7.31 (m, 1H), 7.38 (s,1H), 7.93-7.95 (m, 1H), 8.11-8.13 (m, 2H), 8.58 (s, 1H), 11.48 (brs,1H).

Example 289

To a solution of Compound 288F (50 mg, 0.167 mmol) in dichloromethane (3mL) was added Intermediate C (59 mg, 0.201 mmol) and HATU (95 mg, 0.25mmol). The mixture was stirred at room temperature for 2 hours. It wasconcentrated and the resulting residue was purified with prep-HPLC toafford Compound 289. LC-MS (ESI) m/z: 577 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 2.18-2.19 (m, 4H), 3.01-3.05 (m, 2H), 3.49-3.51 (m, 1H),3.71-3.79 (m, 2H), 3.96-4.02 (m, 2H), 4.18-4.22 (m, 4H), 4.45-4.47 (m,1H), 5.10 (d, J=3.2 Hz, 1H), 5.56 (s, 2H), 6.72-6.73 (m, 2H), 6.97-7.03(m, 2H), 7.16-7.19 (m, 2H), 7.35-7.37 (m, 1H), 7.68-7.70 (m, 1H),8.02-8.04 (m, 1H), 8.18 (s, 1H), 8.73 (s, 1H).

Example 290

A mixture of Compound 290A (2 g, 9.85 mmol) and aminooxysulfonic acid(1.67 g, 14.78 mmol) in ethanol (50 mL) was stirred at room temperaturefor 2 h. The mixture was diluted with DCM (200 mL), washed with water(200 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, andconcentrated to afford Compound 290B.

To a solution of PPh₃ (3.44 g, 13.12 mmol) in DCM (40 mL) was added DDQ(2.98 g, 13.12 mmol) in portions at room temperature and the resultantmixture was stirred for 5 min. Compound 290B (1.89 g, 8.75 mmol) wasadded. The reaction mixture was stirred for 5 min, diluted with DCM (100mL), and filtered. The filtrate was washed with water (100 mL×2) andbrine (50 mL), dried over anhydrous sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, 10% v/v) to give Compound 290C.

A mixture of Compound 290C (198 mg, 1 mmol), Compound 175B (456 mg, 1.5mmol), Pd(PPh₃)₂Cl₂ (70 mg, 0.1 mmol), and K₂CO₃ (256 mg, 2 mmol) indioxane (5 mL) and water (0.5 mL) was stirred at 80° C. for 2 h. Themixture was cooled down and filtered. The precipitate was dissolved inwater and filtered. The filtrate was purified with reverse phasechromatography using eluent (methanol in water, from 0% to 100% v/v) toyield Compound 290D.

A mixture of Compound 290D (100 mg, 0.374 mmol), Intermediate C (111 mg,0.374 mmol), and HATU (171 mg, 0.449 mmol) in DCM (3 mL) was stirred atroom temperature overnight. The mixture was diluted with DCM (100 mL),washed with water (50 mL×2) and brine (50 mL), dried over anhydroussodium sulfate, and concentrated. The crude product was purified withprep-HPLC to give Compound 290. LC-MS (ESI) m/z: 546 [M+H]⁺; ¹H-NMR(acetone-d₆, 400 MHz): δ (ppm) 2.09-2.22 (m, 4H), 3.27-3.40 (m, 3H),3.72-3.77 (m, 2H), 3.87-3.96 (m, 2H), 4.26-4.33 (m, 4H), 4.77-4.82 (m,1H), 5.12-5.13 (m, 1H), 6.84-6.90 (m, 2H), 7.36 (dd, J=1.2 Hz, J₂=8.0Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.72-7.78 (m, 3H), 8.05 (d, J=8.8 Hz,2H), 8.18-8.20 (m, 1H).

Example 291

To a solution of Compound 291A (10.00 g, 47.85 mmol) in DMF (100 mL) wasadded t-BuOK (8.04 mL, 71.77 mmol) at room temperature. The mixture wasstirred room temperature for 2 h and quenched with water (100 mL). Themixture was diluted with ethylacetate (300 mL), washed with water (200mL) and brine (200 mL), dried over anhydrous sodium sulfate, andpurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 0% to 5% v/v) to afford Compound 291B.

To a solution of Compound 291B (11.00 g, 0.042 mol) in THF (30 mL) wasadded dropwise n-BuLi solution (2.5 Min hexane, 16.8 mL, 0.042 mol)under nitrogen at −68° C. The mixture was stirred at −78° C. for 30 minand a solution of Compound A4 (5.50 g, 13.89 mmol) in THF (20 mL) wasadded dropwise under nitrogen at −78° C. The mixture was stirred at −78°C. for 20 min and quenched with saturated aqueous ammonium chloridesolution (100 mL). The mixture was diluted with ethyl acetate (300 mL),washed with water (200 mL) and brine (200 mL), dried over anhydroussodium sulfate, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to furnishCompound 291C.

A solution of Compound 291C (6.00 g, 11.56 mmol) in THF (40 mL), AcOH(120 mL), and water (40 mL) was stirred at 25° C. for 48 h. The mixturewas evaporated to remove solvent, diluted with ethyl acetate (300 mL),washed with water (200 mL) and brine (200 mL), dried over anhydroussodium sulfate, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 0% to 50% v/v) to affordCompound 291D.

To a solution of Compound 291D (3.20 g, 7.90 mmol) in THF (20 mL) wasadded dropwise DIBAL-H solution (1 Min toluene, 15.8 mL, 15.80 mmol)under nitrogen at −80° C. After 30 min, additional DIBAL-H solution (1Min toluene, 15.8 mL, 15.80 mmol) was added dropwise under nitrogen at−80° C. The mixture was stirred under nitrogen at −80° C. for 2 h andquenched with saturated aqueous ammonium chloride solution (200 mL) at−20° C. The mixture was diluted with ethyl acetate (200 mL), washed withwater (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate,and purified with flash column chromatography on silica gel (methanol indichloromethane, from 0% to 5% v/v) to give Compound 291E.

To a solution of Compound 291E (1.10 g, 2.70 mmol) and triethylamine(818 mg, 8.10 mmol) in THF (10 mL) was added dropwise methanesulfonylchloride (370 mg, 3.24 mmol) at −15° C. The mixture was stirred at −15°C. for 1 h. It was quenched with saturated ice water (50 mL), dilutedwith ethyl acetate (200 mL), washed with water (150 mL) and brine (200mL), dried over anhydrous sodium sulfate, and evaporated to affordCompound 291F. The target compound was directly used for the next stepwithout further purification.

A solution of Compound 291F (1.10 g, 2.27 mmol) and pyrrolidine (1.68 g,22.68 mmol) in THF (10 mL) was stirred at 50° C. for 16 h. The mixturewas cooled down to room temperature and diluted with ethyl acetate (200mL). The organic layer was washed with water (200 mL) and brine (200mL), dried over anhydrous sodium sulfate, and purified with flash columnchromatography on silica gel (methanol in dichloromethane, from 0% to 8%v/v) to furnish Compound 291G.

A mixture of Compound 291G (300 mg, 0.65 mmol) and LiOH.H₂O (356 mg,6.52 mmol) in methanol (10 mL) and water (2 mL) was stirred at 80° C.for 16 h. It was diluted with ethyl acetate (200 mL), washed with water(200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, andpurified with reverse phase chromatography using eluent (methanol inwater, from 0% to 100% v/v) to furnish Compound 291H.

A mixture of Compound 291H (110 mg, 0.34 mmol), Intermediate C (82 mg,0.34 mmol), and HATU (190 mg, 0.51 mmol) in DMF (5 mL) was stirred atroom temperature for 16 h. It was diluted with ethyl acetate (120 mL),washed with water (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, and purified with prep-HPLC to afford Compound 291.LC-MS (ESI) m/z: 553 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.33 (s,9H), 1.84-1.93 (m, 2H), 2.00-2.06 (m, 2H), 3.11-3.24 (m, 2H), 3.49-3.53(m, 4H), 4.52-4.57 (m, 1H), 4.91 (s, 1H), 6.08 (s, 1H), 7.21 (d, J=8.4Hz, 1H), 7.27-7.30 (m, 1H), 7.37 (t, J=8.8 Hz, 2H), 7.47 (s, 1H),7.78-7.85 (m, 6H), 8.79 (d, J=9.2 Hz, 1H), 7.43 (s, 1H).

Example 292

To a solution of Compound S (118 mg, 0.40 mmol) in DMF (10 mL) was addedCompound 242F (80 mg, 0.33 mmol), HATU (190 mg, 0.50 mmol), andN,N-diisopropylethylamine (129 mg, 1.0 mmol). The mixture was stirredunder nitrogen at 25° C. overnight. The resulting mixture was quenchedwith saturated aqueous sodium bicarbonate solution (5 mL) and extractedwith ethyl acetate (50 mL×3). The combined organic phases were washedwith water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford a crude compound. The crude productwas purified with prep-HPLC to furnish Compound 292. LC-MS (ESI) m/z:517 [M+H]⁺; ¹H-NMR (DMSO-d₆ 400 MHz): δ (ppm) 0.64-0.76 (m, 4H),1.84-2.00 (m, 4H), 3.09-3.17 (m, 2H), 3.33-3.38 (m, 1H), 3.50-3.56 (m,3H), 3.86-3.90 (m, 1H), 4.43-4.48 (m, 1H), 4.79 (s, 1H), 6.06 (s, 1H),7.14-7.20 (m, 2H), 7.35 (t, J=8.8 Hz, 1H), 7.55 (dd, J=8.8, 2.0 Hz, 1H),8.13 (d, J=8.4 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.63 (d,J=10.0 Hz, 1H), 9.06 (s, 1H).

Example 293

A mixture of Compound 255C (50 mg, 0.18 mmol), HATU (100 mg, 0.27 mmol),and Intermediate H (50 mg, 0.18 mmol) in DMF (3 mL) was stirred at 25°C. for 16 h. The mixture was diluted with ethyl acetate (30 mL), washedwith water (10 mL×2) and brine (10 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with prep-HPLC to furnish Compound293. LC-MS (ESI) m/z: 547 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)1.33 (s, 9H), 2.26-2.45 (m, 2H), 3.36-3.48 (m, 2H), 4.07-4.30 (m, 9H),4.74 (s, 1H), 6.02 (s, 1H), 6.76-6.84 (m, 2H), 7.54-7.56 (m, 2H),7.69-7.71 (m, 2H), 7.78-7.84 (m, 4H), 8.75 (d, J=9.6 Hz, 1H), 9.67 (s,1H).

Example 294

A mixture of Compound 255C (50 mg, 0.18 mmol), HATU (100 mg, 0.27 mmol),and Intermediate C (53 mg, 0.18 mmol) in DMF (3 mL) was stirred at 25°C. for 16 h. The mixture was diluted with ethyl acetate (30 mL), washedwith water (10 mL×2) and brine (10 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with prep-HPLC to furnish Compound294. LC-MS (ESI) m/z: 561 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)1.33 (s, 9H), 1.87-2.03 (m, 4H), 3.12-3.19 (m, 2H), 3.46-3.55 (m, 4H),4.26-4.30 (m, 4H), 4.51-4.52 (m, 1H), 4.79 (s, 1H), 6.06 (s, 1H),6.77-6.84 (m, 2H), 7.54-7.56 (m, 2H), 7.71-7.89 (m, 6H), 8.76 (d, J=9.6Hz, 1H), 9.44 (s, 1H).

Example 295

To a solution of Compound 295A (752 mg, 4 mmol) in 1,4-dioxane (32 mL)and water (4 mL) was added Compound 175B (1.4 g, 4.4 mmol), Pd(dppf)Cl₂(164 mg, 0.2 mmol), and potassium carbonate (1.66 g, 12 mmol) undernitrogen at 20° C. The reaction mixture was stirred at 110° C. for 3hours. The resulting mixture was cooled to 20° C. It was adjusted to pH5 with 2 N HCl and extracted with ethyl acetate (40 mL×3). The combinedorganic layers were concentrated in vacuo without dryness to give thecrude Compound 295B.

To a solution of Compound 295B (78 mg, 0.3 mmol) in DMF (3 mL) anddichloromethane (4 mL) was added Intermediate G (112 mg, 0.36 mmol) andHATU (171 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for3 hours. The mixture was purified with prep-HPLC to yield the productCompound 295. LC-MS (m/z) 551 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)0.74-0.90 (m, 4H), 1.93-2.01 (m, 5H), 2.27 (s, 3H), 2.95-3.10 (m, 2H),3.11-3.3.15 (m, 1H), 3.61-3.65 (m, 3H), 4.00-4.02 (m, 1H), 4.76-4.79 (m,1H), 5.52 (d, J=10.4 Hz, 1H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H),7.28-7.32 (m, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.55 (s, 2H), 7.69 (s, 1H),8.16 (d, J=8.4 Hz, 2H), 9.73 (brs, 1H).

Example 296

To a solution of Compound 175B (600 mg, 1.97 mmol) in THF (20 mL) wasadded LiOH.H₂O (124 mg, 2.96 mmol) dissolved in water (3 mL) at 0° C.The mixture was stirred at room temperature for 4 h. The reactionmixture was treated with water (10 mL) and extracted with ethyl acetate(10 mL). The water layer was adjusted to pH 6 with diluted HCl andextracted with ethyl acetate (25 mL×2). The combined organic layers werewashed with brine (15 mL), dried over anhydrous sodium sulfate, andconcentrated to afford Compound 296A, which was used for the next stepwithout further purification.

A mixture of Compound 296A (480 mg, 1.74 mmol), Intermediate G (594 mg,1.91 mmol), and HATU (991 mg, 2.61 mmol) in dichloromethane (20 mL) wasstirred at 25° C. for 10 h. The mixture was quenched with water (10 mL).The organic layer was washed with brine (50 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to afford a crudecompound. The crude product was purified with prep-HPLC to furnishCompound 296B.

A mixture of 5-bromobenzo[d]thiazole (35 mg, 0.16 mmol), Compound 296B(104 mg, 0.22 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 8.2mol), potassium carbonate (68 mg, 0.49 mmol), water (0.5 mL), and1,4-dioxane (2 mL) was heated under nitrogen atmosphere at 100° C. for 1h. After cooling, water (5 mL) was added, and the mixture was extractedwith ethyl acetate (10 mL×3). The combined organic layers were washedwith brine (5 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude productas a black oil. The oil was purified with prep-HPLC to furnish Compound296. LC-MS (ESI) m/z: 576 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm)0.71-0.73 (m, 2H), 0.81-0.84 (m, 2H), 2.09-2.13 (m, 2H), 2.28 (s, 2H),3.55 (s, 1H), 3.89-3.90 (m, 2H), 4.05-4.08 (m, 4H), 4.94 (s, 1H), 5.21(d, J=2 Hz, 1H), 7.42-7.43 (m, 2H), 7.51 (d, J=1.6 Hz, 1H), 7.91 (dd,J=8.5, 3.0 Hz, 4H), 8.03 (d, J=8.5 Hz, 2H), 8.21 (d, J=9.7 Hz, 1H), 8.31(d, J=8.5 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 9.37 (s, 1H).

Example 297

A mixture of 6-bromobenzo[d]thiazole (30 mg, 0.14 mmol), Compound 296B(90 mg, 0.18 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 8.2μmol), potassium carbonate (58 mg, 0.42 mmol), water (0.5 mL), and1,4-dioxane (2 mL) was heated under nitrogen atmosphere at 100° C. for 1h. After cooling, water (5 mL) was added, and the mixture was extractedwith ethyl acetate (10 mL×3). The combined organic layers were washedwith brine (5 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude productas a black oil. The oil was purified with prep-HPLC to furnish Compound297. LC-MS (ESI) m/z: 576 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm)0.60-0.86 (m, 4H), 2.06-2.38 (m, 4H), 3.27 (s, 1H), 3.52-3.64 (m, 2H),3.89-3.91 (m, 2H), 4.01 (d, J=5.7 Hz, 1H), 4.06-4.16 (m, 2H), 4.92-4.97(m, 1H), 5.20 (d, J=2.1 Hz, 1H), 7.35-7.45 (m, 2H), 7.49 (d, J=1.7 Hz,1H), 7.83-7.90 (m, 2H), 7.95 (dd, J=8.6, 1.8 Hz, 1H), 8.03 (d, J=8.6 Hz,2H), 8.19-8.23 (m, 2H), 8.55 (d, J=1.6 Hz, 1H), 9.36 (s, 1H).

Example 298

To a mixture of Compound 298A (2.96 g, 0.01 mol), 4-fluorophenylboronicacid (2 g, 1.32 mol), and K₃PO₄ (6.4 g, 0.03 mol) in 1,2-dimethoxyethane(80 mL) was added Pd(dppf)Cl₂ (733 mg, 1.0 mmol). The reaction mixturewas stirred under nitrogen at room temperature overnight. The resultingmixture washed with brine (100 mL), dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 10%to 50% v/v) to furnish Compound 298B.

To a solution of Compound 298B (2.64 g, 10 mmol) in THF (30 mL) wasadded dropwise n-BuLi solution (2.5 Min hexane, 4 mL, 10 mmol) undernitrogen at −78° C. The mixture was stirred at −78° C. for 0.5 h and thesolution was added to a solution of diethyl oxalate (3 g, 20 mmol) inTHF (20 mL) under nitrogen at −78° C. The mixture was stirred at roomtemperature overnight and quenched with saturated aqueous ammoniumchloride solution (40 mL). The reaction mixture was extracted with ethylacetate (50 mL×3), washed with water (100 mL) and brine (100 mL), driedover anhydrous sodium sulfate, and concentrated. The residue waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 10% to 50% v/v) to give Compound 298C.

To a solution of Compound 298C (2.8 g, 0.01 mol) in ethanol/water (40mL/10 mL) was added LiOH H₂O (840 mg, 0.02 mol). The mixture was stirredat room temperature for about 2 h until completion by thin layerchromatography analysis. The reaction mixture was acidified to pH 2 withaqueous HCl solution (1.0 N, 40 mL) and extracted with ethyl acetate (30mL×2). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated toafford Compound 298D.

To a mixture of Compound 298D (126 mg, 0.5 mmol) and Intermediate G (155mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith prep-HPLC to furnish Compound 298. LC-MS (ESI) m/z: 551 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.62-0.87 (m, 4H), 1.88-2.04 (m, 4H),2.26 (s, 3H), 3.13-3.21 (m, 2H), 3.50-3.56 (m, 4H), 3.88-3.89 (m, 1H),4.54-4.56 (m, 1H), 4.87 (s, 1H), 6.05 (s, 1H), 7.27-7.45 (m, 8H), 7.53(d, J=6.8 Hz, 1H), 7.76 (s, 1H), 8.80 (d, J=9.2 Hz, 1H), 9.40 (s, 1H).

Example 299

To a mixture of Compound 298D (130 mg, 0.5 mmol) and Intermediate C (143mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was washed with brine (30 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedwith prep-HPLC to furnish Compound 299. LC-MS (ESI) m/z: 537 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.86-2.04 (m, 4H), 2.27 (s, 3H),3.11-3.18 (m, 2H), 3.42-3.54 (m, 4H), 4.23-4.28 (m, 4H), 4.49 (s, 1H),4.77 (s, 1H), 6.04 (s, 1H), 6.75 (s, 1H), 6.81-6.84 (m, 1H), 7.31-7.35(m, 3H), 7.42-7.46 (m, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.80 (s, 1H), 8.75(d, J=9.6 Hz, 1H), 9.30 (s, 1H).

Example 300

A mixture of Compound 133D (110 mg, 0.37 mmol), Intermediate W (90 mg,0.37 mmol), and HATU (182 mg, 0.48 mmol) in dichloromethane (10 mL) wasstirred at 10° C. for 15 h. And then it was treated with water (10 mL)and extracted with dichloromethane (10 mL×3 mL). The organic layers werewashed with water (20 mL×3), dried over anhydrous sodium sulfate,concentrated in vacuo, and purified with prep-HPLC to yield Compound300. LC-MS (ESI) m/z: 525 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm)2.58 (s, 1H), 2.70-2.77 (m, 1H), 3.88-4.01 (m, 2H), 4.22-4.38 (m, 4H),4.49-4.64 (m, 4H), 4.71-4.77 (m, 1H), 5.12 (s, 1H), 5.47 (s, 1H), 6.94(d, J=1.6 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 7.30 (t, J=8.8 Hz, 2H),7.77-7.84 (m, 4H), 7.99 (d, J=8.4 Hz, 2H), 8.11 (d, J=9.6 Hz, 1H), 9.19(s, 1H).

Example 301

A mixture of Compound 175A (512 mg, 2 mmol), 4-cyanophenylboronic acid(294 mg, 2 mmol), potassium carbonate (828 mg, 6 mmol), and Pd(dppf)Cl₂(40 mg, 0.08 mmol) in dioxane (20 mL) and water (4 mL) was stirred undernitrogen at 100° C. overnight. The solution was cooled down to roomtemperature, adjusted to pH 4 with aqueous hydrochloric acid solution (6N, 2 mL), and extracted with ethyl acetate (100 mL×3). The combinedorganic layers were washed with water (50 mL) and brine (50 mL), driedover anhydrous sodium sulfate, filtered, and evaporated to affordCompound 301A.

A mixture of Compound 301A (100 mg, 0.4 mmol), HATU (273 mg, 0.72 mmol),and Intermediate G (124 mg, 0.4 mmol) in dichloromethane (10 mL) and DMF(2 mL) was stirred at 25° C. overnight. The solution was extracted withethyl acetate (50 mL×2). The combined organic phases were washed withwater (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to give a residue. The residue was purifiedwith prep-HPLC to furnish Compound 301. LC-MS (ESI) m/z: 544 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.66-0.82 (m, 4H), 1.88-2.02 (m, 4H),3.12-3.21 (m, 2H), 3.47-3.64 (m, 4H), 3.88-3.93 (m, 1H), 4.53-4.61 (m,1H), 4.87 (s, 1H), 6.05 (s, 1H), 7.33-7.43 (m, 3H), 7.85-7.86 (m, 3H),7.95-8.03 (m, 5H), 8.81-8.83 (m, 1H), 9.39 (s, 1H).

Example 302

To a solution of Compound 302A (1 g, 0.59 mmol) in CHCl₃ (6 mL) wasadded bromine (0.68 mL, 13.26 mmol) at 0° C. The mixture was stirred at25° C. for 48 h. It was poured into aq. Na₂S₂O₃ (50 mL) and extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine (30 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo to furnish the crude product. It wasrecrystallized from methanol to give Compound 302B.

To a solution of Compound 302B (324 mg, 1 mmol) in THF (20 mL) was addedn-BuLi (2.5 M, 0.4 mL, 1.06 mmol) under nitrogen at −60° C. It wasstirred at −60° C. for 0.5 h. And then a solution of diethyl oxalate(0.4 mL, 3 mmol) in THF (5 mL) was added. The mixture was stirred at−60° C. for 0.5 h, quenched with saturated ammonium chloride solution(200 mL), extracted with ethyl acetate (20 mL×3), washed with brine (20mL), dried over anhydrous sodium sulfate, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v)to furnish Compound 302C.

To a solution of Compound 302C (39 mg, 0.11 mmol) in THF/water (6 mL,5:1, v/v) was added LiOH H₂O (52 mg, 0.12 mmol). The mixture was stirredat 0° C. for 1 h. After the reaction was completed, water (20 mL) wasadded. It was extracted with ethyl acetate (20 mL). The water wasadjusted to pH 2. It was extracted with ethyl acetate (20 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo to give the crude Compound 302D.

A mixture of Compound 302D (35 mg, 0.11 mmol), Intermediate G (43 mg,0.14 mmol), and HATU (54 mg, 0.14 mmol) in DMF (4 mL) was stirred at 10°C. for 3 h. And then it was purified with prep-HPLC to give Compound302. LC-MS (ESI) m/z: 611 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm)0.58-0.83 (m, 4H), 2.07-2.16 (m, 2H), 2.24 (s, 2H), 3.45 (s, 2H),3.80-3.85 (m, 2H), 3.96 (s, 3H), 4.90 (s, 1H), 5.20 (s, 1H), 7.36 (d,J=8.0 Hz, 1H), 7.44 (dd, J=8.4 Hz, J₂=1.6 Hz, 1H), 7.53 (d, J=2.0 Hz,1H), 7.69-7.77 (m, 3H), 8.17 (dd, J=8.4 Hz, J₂=1.6 Hz, 1H), 8.23 (d,J=9.6 Hz, 1H), 8.43 (d, J=2 Hz, 1H), 8.84 (d, J=1.2 Hz, 1H), 10.19 (brs,1H).

Example 303

A mixture of Compound 303A (191 mg, 0.83 mmol), K₂CO₃ (456 mg, 3.3mmol), and D20 (12 mL) was stirred at 110° C. overnight. The mixture wasacidified with the addition of 1 M HCl, extracted with DCM (20 mL×2),dried over anhydrous sodium sulfate, and concentrated to furnishCompound 303B.

A mixture of Compound 303B (145 mg, 0.63 mmol) in SOCl₂ (4.5 mL) wasstirred at 25° C. for 2 h. The mixture was concentrated to give Compound303C (160 mg, yield 100%) as a yellow oil, which was directly used forthe next step without further purification.

A solution of Intermediate G (200 mg, 0.63 mmol) in CD₃OD was evaporatedto dryness and the residue was dissolved CDCl₃ (8 mL). The solution wasadded to Compound 303C (200 mg, 0.63 mmol). The mixture was stirred at25° C. for 0.5 h. The reaction mixture was treated with water (20 mL),extracted with DCM (50 mL×2), washed with brine (50 mL), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to give Compound 303. LC-MS (ESI) m/z: 525.2[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.57-0.66 (m, 4H), 2.02-2.23(m, 4H), 3.13-3.30 (m, 2H), 3.48-3.68 (m, 4H), 3.80-3.88 (m, 1H),4.51-4.54 (m, 1H), 4.87 (d, J=2.4 Hz, 1H), 7.06-7.20 (m, 6H), 7.42-7.49(m, 3H), 7.62-7.66 (m, 2H).

Example 304

To a solution of Compound 288E (150 mg, 0.45 mmol) in THF (1 mL) wasadded dropwise 1 N lithium hydroxide (1 mL, 1 mmol). The reactionmixture was stirred at room temperature for 2 h. After the reactionmixture was concentrated, 2 N HCl (1 mL) added to adjust pH 7, andextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed with water (5 mL) and brine (5 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to furnish Compound 304A.

To a solution of Compound 304A (50 mg, 0.167 mmol) in dichloromethane (3mL) was added Intermediate G (62 mg, 0.201 mmol) and HATU (95 mg, 0.25mmol). The mixture was stirred at room temperature for 2 h. It wasconcentrated and the resulting residue was purified with prep-HPLC toafford Compound 304. LC-MS (ESI) m/z: 591 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 0.74-0.76 (m, 4H), 2.13-2.15 (m, 4H), 3.01-3.05 (m, 1H),3.50-3.58 (m, 1H), 3.59-3.81 (m, 3H), 3.87-4.01 (m, 2H), 4.53-4.57 (m,1H), 5.11-5.16 (m, 1H), 5.56 (s, 2H), 7.05-7.09 (m, 2H), 7.21-7.23 (m,1H), 7.27-7.33 (m, 3H), 7.36-7.37 (m, 1H), 7.66-7.68 (s, 1H), 7.79-7.80(m, 1H), 8.12 (s, 2H), 8.58 (s, 1H).

Example 305

To a solution of Compound 304A (50 mg, 0.167 mmol) in dichloromethane (3mL) was added Intermediate C (59 mg, 0.201 mmol) and HATU (95 mg, 0.25mmol). The mixture was stirred at room temperature for 2 h. It waspurified with prep-HPLC and prep-TLC to afford Compound 305. LC-MS (ESI)m/z: 577 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 1.82-1.85 (m, 4H),2.75-2.84 (m, 4H), 3.01-3.04 (m, 2H), 4.16-4.33 (m, 5H), 5.03 (d, J=1.6Hz, 1H), 5.57 (s, 2H), 6.69-6.74 (m, 2H), 7.04-7.09 (m, 2H), 7.26-7.32(m, 2H), 7.42-7.45 (m, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.92 (d, J=8.8 Hz,1H), 8.09 (s, 1H), 8.93 (s, 1H).

Example 306

To a solution of Compound 256A (640 mg, 2.69 mmol) in dry THF (10 mL)was added dropwise n-BuLi solution (2.5 Min hexane, 1.1 mL, 2.72 mmol)under nitrogen at −78° C. The mixture was stirred at −78° C. for 30 minand diethyl oxalate (0.91 mL, 6.73 mmol) was added quickly to the abovemixture. The mixture was stirred at −78° C. for 30 min, quenched withsaturated aqueous ammonium chloride solution (10 mL), and extracted withethyl acetate (80 mL×2). The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 0% to 5% v/v) to furnishCompound 306A.

To a solution of Compound 306A (490 mg, 2.11 mmol) in methanol (5 mL)was added LiOH H₂O (177 mg, 4.22 mmol) in water (5 mL) and the mixturewas stirred at room temperature overnight. After completion of thereaction, the mixture was adjusted to pH 6 with aqueous HCl solution (3N) and concentrated in vacuo. The residue was in lyophilization toafford Compound 306B.

A mixture of Compound 306B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol),and Intermediate G (93 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10°C. for 18 h. The mixture was directly purified with prep-HPLC to yieldCompound 306. LC-MS (ESI) m/z: 525 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 0.59-0.81 (m, 4H), 1.47 (d, J=6.4 Hz, 3H), 1.52 (d, J=6.8 Hz, 3H),1.87-2.04 (m, 4H), 3.06-3.22 (m, 2H), 3.47-3.56 (m, 4H), 3.87-3.91 (m,1H), 4.54-4.56 (m, 1H), 4.86 (d, J=2.8 Hz, 1H), 5.01-5.05 (m, 1H), 6.07(brs, 1H), 7.33-7.39 (m, 2H), 7.45-7.48 (m, 2H), 7.83 (d, J=8.8 Hz, 1H),8.23 (s, 1H), 8.35 (s, 1H), 8.81 (d, J=9.6 Hz, 1H), 9.34 (brs, 1H).

Example 307

A mixture of Compound 306B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol),and Intermediate C (93 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10°C. for 18 h. The mixture was directly purified with prep-HPLC to affordCompound 307. LC-MS (ESI) m/z: 511 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.49 (d, J=6.8 Hz, 3H), 1.52 (d, J=6.8 Hz, 3H), 1.87-1.89 (m, 2H),2.02-2.04 (m, 2H), 3.10-3.21 (m, 2H), 3.43-3.55 (m, 4H), 4.21-4.31 (m,4H), 4.48-4.55 (m, 1H), 4.77 (d, J=3.2 Hz, 1H), 5.02-5.08 (m, 1H), 6.77(s, 1H), 6.84 (dd, J=11.6, 1.6 Hz, 1H), 7.50 (dd, J=8.4, 1.2 Hz, 1H),7.86 (d, J=8.8 Hz, 1H), 8.24 (s, 1H), 8.38 (s, 1H), 8.79 (d, J=9.6 Hz,1H), 9.30 (brs, 1H).

Example 308

To a solution of Intermediate C (118 mg, 0.40 mmol) in DMF (10 mL) wasadded Compound 242F (80 mg, 0.33 mmol), HATU (190 mg, 0.50 mmol), andN,N-diisopropylethylamine (129 mg, 1.0 mmol). The mixture was stirredunder nitrogen at 25° C. overnight. The resulting mixture was quenchedwith saturated aqueous sodium bicarbonate solution (5 mL) and extractedwith ethyl acetate (50 mL×3). The combined organic phases were washedwith water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford a crude compound. The crude productwas purified with prep-HPLC to furnish Compound 308. LC-MS (ESI) m/z:519 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 2.00-2.04 (m, 2H),2.15-2.18 (m, 2H), 3.19-3.29 (m, 2H), 3.46-3.50 (m, 1H), 3.67-3.81 (m,3H), 4.11-4.23 (m, 4H), 4.29-4.35 (m, 2H), 4.54-4.57 (m, 1H), 4.85 (d,J=3.2 Hz, 1H), 6.76-6.81 (m, 2H), 7.46 (dd, J=8.8, 2.0 Hz, 1H), 7.98 (d,J=8.8 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 8.48 (s, 1H).

Example 309

To a solution of Compound 309A (31.7 g, 154 mmol) in1-methyl-2-pyrrolidinone (300 mL) was added cesium carbonate (100.4 g,308 mmol) and bromocyclopentane (68.4 g, 462 mmol). The mixture wasstirred for 24 h while keeping inner temperature between 145° C. and155° C. After the reaction was cooled to ambient temperature, the darksolution was diluted with water (400 mL) and extracted with a mixture ofethyl acetate in petroleum ether (15% v/v) (300 mL×3). The combinedorganic phases were washed with brine (150 mL×4), dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude productas a brown oil. The crude product was purified with flash columnchromatography on silica gel (petroleum ether) to furnish Compound 309B.

To a solution of Compound 309B (32 g, 116.8 mmol) in dry THF (360 mL)maintained at −70° C. was added n-BuLi (2.5 Min hexane, 46.7 mL)dropwise under nitrogen atmosphere over a period of 20 minutes. Afterthe reaction was stirred for 40 minutes at −70° C., Compound A4 (18.5 g,46.7 mmol) dissolved in dry THF (50 mL) was added slowly to the coldsolution at a rate that maintained the internal temperature between-70°C. and −50° C. After the addition was complete, the solution was left tostir for 1 h. The reaction was quenched with saturated ammonium chloridesolution (400 mL), extracted with ethyl acetate (400 mL×3), washed withwater (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to furnish the crude Compound (3). The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 5% to 20% v/v) to furnishCompound 309C.

A solution of Compound 309C (14.1 g, 26.5 mmol) in a mixture oftetrahydrofuran water and glacial acetic acid (450 mL, 1/1/3, v/v/v) wasstirred at 25° C. for 30 h. After that, the reaction mixture wasconcentrated under reduced pressure to remove excess solvent. Thereaction the residue was poured into ice water (20 g) and adjusted pH7-8 with aqueous sodium hydroxide (1 N) and saturated aqueous sodiumbicarbonate solution. The solution was extracted with ethyl acetate (100mL×3). The combined organic phases were washed with brine (50 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to afford thecrude target compound, which was further purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 30%to 50% v/v) to give Compound 309D.

To a solution of Compound 309D (10.0 g, 24.0 mmol) in dry THF (500 mL)maintained at −78° C. was added diisobutylaluminum hydride (1.0 Mintoluene, 96 mL) dropwise under nitrogen atmosphere over a period of 15minutes. After the reaction was stirred at −70° C. for 1 h, a solutionof HCl (2 N, 100 mL) was added to the mixture slowly. The reactionmixture was extracted with ethyl acetate (100 mL×3), dried overanhydrous sodium sulfate, filtered, and concentrated to afford the crudetarget compound, which was further purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 50%to 150% v/v) to furnish Compound 309E.

To a solution of Compound 309E (9.25 g, 24.0 mmol) dissolved intetrahydrofuran (300 mL) was added triethylamine (7.3 g, 72.0 mmol). Themixture was cooled to −30° C., and then methanesulfonyl chloride (3 g,26.4 mmol) was added dropwise over a period of 15 minutes. After theaddition was complete, the reaction was stirred at −30° C. for 1.5 h,diluted with water (150 mL), and extracted with ethyl acetate (150mL×2). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated toafford crude Compound 309F, which was directly used for the next stepwithout further purification.

To a solution of Compound 309F 11.2 g, purity 70%) in tetrahydrofuran(50 mL) was added pyrrolidine (13.5 g, 190 mmol). The reaction mixturewas allowed to heat to 50° C. for 16 h. The mixture was diluted withwater (100 mL), extracted with ethyl acetate (250 mL×2), washed withbrine (50 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish a crude compound. The crude product was purifiedwith flash column chromatography on silica gel (methanol indichloromethane, 5% v/v) to give Compound 309G.

To a solution of Compound 309G (800 mg, 1.69 mmol) in ethanol (12 mL)and water (2 mL) was added LiOH H₂O (284 mg, 6.76 mmol). The mixture washeated to 80° C. and stirred for 16 h. The reaction mixture was dilutedwith water (15 mL) and extracted with dichloromethane (50 mL×2). Thecombined organic phases were washed with water (50 mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish Compound 309H, which was directly used for the next step withoutfurther purification.

To a solution of Compound 309H (200 mg, 0.6 mmol), Intermediate C (146mg, 0.6 mmol), and HATU (456 mg, 1.2 mmol) in N,N-dimethylformamide (3mL) was stirred at room temperature for 1 h. The reaction solution waspurified with prep-HPLC to furnish Compound 309. LC-MS (ESI) m/z: 565[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.55-1.74 (m, 6H), 1.87-202(m, 6H), 3.05-3.54 (m, 6H), 4.51-4.91 (m, 3H), 6.01 (d, J=4.4 Hz, 1H),7.12 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.8, 2.0 Hz, 1H), 7.33-7.42 (m, 3H),7.70-7.81 (m, 6H), 8.81 (d, J=10.0 Hz, 1H), 9.34 (s, 1H).

Example 310

A mixture of Compound 310A (2.11 g, 10 mmol), 2-bromopropane (2.46 g, 20mmol), and K₂CO₃ in DMF (40 mL) was stirred at 100° C. overnight. Themixture was diluted with ethyl acetate (200 mL), washed with water (200mL×4) and brine (100 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 33% v/v) to afford Compound 310Band Compound 310C.

A mixture of Compound 310C (330 mg, 1.3 mmol), Compound 175B (594 mg,1.96 mmol), Pd(PPh₃)₂Cl₂ (91 mg, 0.13 mmol), and K₂CO₃ (333 mg, 2.6mmol) in dioxane (6 mL) and water (0.6 mL) was stirred at 80° C. for 2h. The mixture was cooled down and filtered. The precipitate wasdissolved in water and washed with ethyl acetate (50 mL). The aqueouslayer was adjusted to pH 2 with concentrated HCl and extracted withethyl acetate (200 mL). The organic layer was dried over anhydroussodium sulfate and concentrated to yield Compound 310D.

A mixture of Compound 310D (100 mg, 0.31 mmol), Intermediate C (96 mg,0.31 mmol), and HATU (177 mg, 0.465 mmol) in DCM (2 mL) was stirred atroom temperature overnight. The mixture was diluted with DCM (100 mL),washed with water (50 mL×2) and brine (50 mL), dried over anhydroussodium sulfate, and concentrated. The crude product was purified withprep-HPLC to give Compound 310. LC-MS (ESI) m/z: 615 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.64-0.70 (m, 2H), 0.79-0.85 (m, 2H), 1.52(d, J=6.4 Hz, 6H), 1.86-1.92 (m, 2H), 2.01-2.06 (m, 2H), 2.71 (s, 3H),3.09-3.24 (m, 2H), 3.46-3.59 (m, 4H), 3.93-3.98 (m, 1H), 4.56-4.60 (m,1H), 4.86-4.91 (m, 2H), 6.04-6.08 (m, 1H), 7.35-7.46 (m, 3H), 7.60-7.62(m, 1H), 7.67-7.69 (m, 1H), 7.74-7.76 (m, 2H), 7.81-7.84 (m, 2H), 8.13(s, 1H), 8.81 (d, J=10.0 Hz, 1H), 9.43 (brs, 1H).

Example 311

To a solution of Compound 256B (717 mg, 3.0 mmol) in THF (20 mL) wasadded dropwise n-BuLi (1.2 mL, 2.5 Min hexane, 3.0 mmol) under nitrogenatmosphere at −60° C. The reaction mixture was stirred at the sametemperature for 30 minutes. Compound diethyl oxalate (1.31 g, 9.0 mmol)was added. The resulting mixture was stirred at −60° C. for anadditional 30 minutes. The reaction mixture was quenched with saturatedammonium chloride solution (30 mL) and extracted with ethyl acetate (40mL×2). The combined organic phases were dried over anhydrous sodiumsulfate, filtered, evaporated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to give Compound 311A.

To a solution of Compound 311A (20 mg, 0.077 mmol) in MeOH (2 mL) wasadded LiOH.H₂O (4 mg, 0.095 mmol) and water (1.0 mL). The reactionmixture was stirred at 15° C. for 4 h. The reaction mixture wasneutralized with HCl (1 N). The resulting mixture was evaporated. Theresidue was dissolved in water (3 mL). The mixture was extracted withethyl acetate (5 mL×2), dried over anhydrous sodium sulfate, filtered,and evaporated to give Compound 311B.

To a solution of Compound 311B (17 mg, 0.073 mmol) in DMF (3 mL) wasadded Intermediate G (22 mg, 0.073 mmol) and HATU (28 mg, 0.073 mmol).The reaction mixture was stirred at 20° C. for 2 h. The mixture waspurified with prep-HPLC to yield Compound 311. LC-MS (m/z) 525 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.62-0.66 (m, 2H), 0.80-0.81 (m, 2H),1.57 (d, J=10.8 Hz, 6H), 1.87-1.89 (m, 2H), 2.01-2.03 (m, 2H), 3.11-3.22(m, 2H), 3.47-3.55 (m, 4H), 3.90-3.93 (m, 1H), 4.55-4.60 (m, 2H),4.85-4.91 (m, 2H), 7.35-7.44 (m, 3H), 7.64-7.67 (m, 2H), 8.27 (s, 1H),8.64 (s, 1H), 8.71-8.74 (m, 1H), 9.39 (brs, 1H).

Example 312

A mixture of Compound 316B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol),and Intermediate C (93 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10°C. for 18 h. The mixture was directly purified with prep-HPLC to affordCompound 312. LC-MS (ESI) m/z: 511 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.57 (d, J=6.8 Hz, 6H), 1.88-2.04 (m, 4H), 3.10-3.20 (m, 2H),3.43-3.56 (m, 4H), 4.24-4.30 (m, 4H), 4.51-4.55 (m, 1H), 4.77 (d, J=2.4Hz, 1H), 4.86-4.96 (m, 1H), 6.76 (s, 1H), 6.82 (dd, J=11.6, 2.0 Hz, 1H),7.45 (dd, J=8.4, 1.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 8.29 (m, 1H), 8.56(s, 1H), 8.71 (d, J=9.6 Hz, 1H), 9.29 (brs, 1H).

Example 313

To a solution of 4-bromo-2-chlorophenol (5.0 g, 24 mmol) in1-methyl-2-pyrrolidinone (70 mL) was added cesium carbonate (15.6 g, 48mmol) and bromocyclobutane (9.7 g, 72 mmol). The mixture was stirred for24 h while keeping inner temperature between 145° C. and 155° C. Afterthe reaction mixture was cooled to ambient temperature, the darksolution was diluted with water (100 mL) and extracted with a mixture ofethyl acetate in petroleum ether (15% v/v) (100 mL×3). The combinedorganic phases were washed with brine (150 mL×4), dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude productas a brown oil. The crude product was purified with flash columnchromatography on silica gel (petroleum ether) to furnish Compound 313A.

To a solution of Compound 313A (15.6 g, 60 mmol) in dry THF (500 mL)maintained at −70° C. was added n-BuLi (60 mmol, 2.4 M in hexane, 25 mL)dropwise under nitrogen atmosphere over a period of 20 minutes. Afterthe reaction mixture was stirred at −70° C. for 40 minutes, Compound A4(7.9 g, 20 mmol) dissolved in dry THF (50 mL) was added slowly to thecold solution at a rate that maintained the internal temperature between−70° C. and −50° C. After the addition was complete, the solution wasleft to stir for 1 h. The reaction mixture was quenched with saturatedammonium chloride solution (100 mL) and extracted with ethyl acetate(100 mL×3). The organic phase was washed with water (100 mL) and brine(100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish the crude Compound 313B. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 5% to 10% v/v) to furnish Compound 313B.

A solution of Compound 313B (8.5 g, 16.4 mmol) in a mixture oftetrahydrofuran, water, and glacial acetic acid (250 mL, 1/1/3, v/v/v)was stirred at 25° C. for 72 h. The reaction mixture was concentratedunder reduced pressure to remove excess solvent. The residue was pouredinto ice water (20 g) and adjusted to pH 7-8 with aqueous sodiumhydroxide (1 N) and saturated aqueous sodium bicarbonate solution. Themixture was extracted with ethyl acetate (100 mL×3). The combinedorganic phases were washed with brine (100 mL), dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude targetcompound, which was further purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, from 30% to 50% v/v) togive Compound 313C.

To a solution of Compound 313C (1.2 g, 2.97 mmol) in dry THF (700 mL)maintained at −78° C. was added diisobutylaluminum hydride (1.0 Mintoluene, 11.9 mL) dropwise under nitrogen atmosphere over a period of 15minutes. After the reaction mixture was stirred at −70° C. for 1 h, asolution of HCl (2 N, 20 mL) was added to the mixture slowly. Thereaction mixture was extracted with ethyl acetate (30 mL×3), dried overanhydrous sodium sulfate, filtered, and concentrated to afford the crudetarget compound, which was further purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 50%to 150% v/v) to furnish Compound 313D.

To a solution of Compound 313D (607 mg, 1.50 mmol) dissolved in THF (15mL) was added triethylamine (454 mg, 4.50 mmol). The mixture was cooledto −30° C., and then methanesulfonyl chloride (188 mg, 1.65 mmol) wasadded dropwise over a period of 15 minutes. After the addition wascomplete, the reaction mixture was stirred at −30° C. for 1.5 h, dilutedwith water (30 mL), and extracted with ethyl acetate (30 mL×2). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to afford Compound313E, which was directly used for the next step without furtherpurification.

To a solution of Compound 313E (690 mg, 1.42 mmol) in THF (30 mL) wasadded pyrrolidine (1.0 g, 14.2 mmol). The reaction mixture was allowedto heat to 50° C. for 16 h. The mixture was diluted with water (15 mL),extracted with ethyl acetate (75 mL×2), washed with brine (25 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to furnish acrude compound. The crude product was purified with flash columnchromatography on silica gel (methanol in dichloromethane, 5% v/v) togive Compound 313F.

To a solution of Compound 313F (330 mg, 0.72 mmol) in ethanol (6 mL) andwater (1 mL) was added LiOH.H₂O (121 mg, 2.88 mmol). The mixture washeated to 80° C. and stirred for 10 h. The reaction mixture was dilutedwith water (10 mL) and extracted with dichloromethane (20 mL×2). Thecombined organic phases were washed with water (20 mL) and brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish Compound 313G, which was directly used for the next step withoutfurther purification.

To a solution of Compound 313G (75 mg, 0.23 mmol) in dichloromethane (5mL) was added Intermediate C (56 mg, 0.23 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (131 mg, 0.345 mmol). The reaction mixturewas stirred at 20° C. for 5 h. The resulting mixture was washed withbrine. The organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated. The crude product was purified withprep-HPLC to yield Compound 313. LC-MS (ESI) m/z: 551 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 1.60-1.63 (m, 1H), 1.74-1.77 (m, 1H),1.89-1.91 (m, 2H), 2.00-2.08 (m, 4H), 2.41-2.45 (m, 2H), 3.15-3.22 (m,2H), 3.45-3.48 (m, 3H), 3.55-3.56 (m, 2H), 4.55-4.56 (m, 1H), 4.71-4.75(m, 1H), 4.87 (s, 1H), 6.03 (s, 1H), 6.95-6.98 (m, 1H), 7.26-7.29 (m,1H), 7.36-7.40 (m, 2H), 7.44-7.45 (m, 1H), 7.73-7.76 (m, 3H), 7.80-7.84(m, 2H), 8.79-8.81 (m, 1H), 9.47 (brs, 1H).

Example 314

A mixture of Compound 310B (330 mg, 1.3 mmol), Compound 175B (594 mg,1.96 mmol), Pd(PPh₃)₂Cl₂ (91 mg, 0.13 mmol), and K₂CO₃ (333 mg, 2.6mmol) in dioxane (6 mL) and water (0.6 mL) was stirred at 80° C. for 2h. The mixture was cooled down, diluted with ethyl acetate (200 mL),washed with water (200 mL×4) and brine (100 mL), dried over anhydroussodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v)to yield Compound 314A.

A mixture of Compound 314A (240 mg, 0.68 mmol) and LiOH.H₂O (43 mg, 1.03mmol) in THF (5 mL) and water (0.5 mL) was stirred at room temperatureovernight. The mixture was diluted with water (50 mL), adjusted to pH 2with concentrated HCl, and extracted with ethyl acetate (200 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedto yield Compound 314B.

A mixture of Compound 314B (120 mg, 0.372 mmol), Intermediate G (115 mg,0.372 mmol), and HATU (211 mg, 0.555 mmol) in dichloromethane (3 mL) wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (100 mL), washed with water (50 mL×2) and brine (50 mL),dried over anhydrous sodium sulfate, and concentrated. The crude productwas purified with prep-HPLC to give Compound 314. LC-MS (ESI) m/z: 615[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.63-0.70 (m, 2H), 0.79-0.86(m, 2H), 1.48 (d, J=6.4 Hz, 6H), 1.87-1.93 (m, 2H), 2.02-2.07 (m, 2H),2.57 (s, 3H), 313-3.24 (m, 2H), 3.49-3.60 (m, 4H), 3.93-3.98 (m, 1H),4.52-4.61 (m, 1H), 4.89-5.00 (m, 2H), 6.06-6.07 (m, 1H), 7.35-7.46 (m,3H), 7.73-7.79 (m, 4H), 7.82-7.86 (m, 2H), 8.11 (d, J=7.2 Hz, 1H),8.81-8.83 (m, 1H), 9.43 (brs, 1H).

Example 315

To a solution of Compound 295B (78 mg, 0.3 mmol) in DMF (1.5 mL) anddichloromethane (4 mL) was added Intermediate C (100 mg, 0.33 mmol) andHATU (171 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for3 hours. The mixture was purified with prep-HPLC to yield Compound 315.LC-MS (m/z) 537 [M+H]⁺; 1H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.80-1.87 (m,4H), 2.25 (s, 3H), 3.04-3.15 (m, 2H), 3.44-3.53 (m, 3H), 4.25-4.27 (m,5H), 4.47-4.52 (m, 1H), 4.76 (s, 1H), 6.05 (s, 1H), 6.76-6.80 (m, 2H),7.17-7.26 (m, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 8.76(d, J=10 Hz, 1H), 9.30 (brs, 1H).

Example 316

To a solution of Compound 256B (640 mg, 2.69 mmol) in dry THF (10 mL)was added dropwise n-BuLi solution (2.5 Min hexane, 1.1 mL, 2.72 mmol)under nitrogen at −78° C. The mixture was stirred at −78° C. for 30 minand diethyl oxalate (0.91 mL, 6.73 mmol) was added quickly to the abovemixture. The mixture was stirred at −78° C. for 30 min, quenched withsaturated aqueous ammonium chloride solution (10 mL), and extracted withethyl acetate (80 mL×2). The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 0% to 20% v/v) to furnishCompound 316A.

To a solution of Compound 316A (180 mg, 0.69 mmol) in methanol (3 mL)was added LiOH H₂O (44 mg, 1.04 mmol) in water (3 mL) and the mixturewas stirred at room temperature overnight. After completion of thereaction, the mixture was adjusted to pH 3 with aqueous HCl solution (3N) and concentrated in vacuo. The residue was in lyophilization toafford Compound 316B.

A mixture of Compound 316B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol),and Intermediate G (93 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10°C. for 18 h. The mixture was directly purified with prep-HPLC to yieldCompound 316. LC-MS (ESI) m/z: 525 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ(ppm) 0.67-0.81 (m, 4H), 1.67 (d, J=6.8 Hz, 6H), 2.04-2.22 (m, 4H),3.22-3.28 (m, 2H), 3.55-3.61 (m, 1H), 3.68-3.89 (m, 4H), 4.66-4.69 (m,1H), 4.87-4.90 (m, 1H), 4.95 (d, J=3.2 Hz, 1H), 7.37 (s, 2H), 7.44-7.47(m, 2H), 7.75 (d, J=8.8 Hz, 1H), 8.37 (s, 1H), 8.39 (s, 1H).

Example 317

To a solution of Compound 310B (245 mg, 0.97 mmol) in dry THF (12 mL)maintained at −70° C. was added n-BuLi (2.5 Min hexane, 0.4 mL) dropwiseunder nitrogen atmosphere over a period of 5 minutes. After the reactionmixture was stirred at −70° C. for 40 minutes, diethyl oxalate (355 mg,2.4 mmol) was added in one portion. The mixture was stirred at 60° C.for 2 hours. The solution was quenched with saturated ammonium chloridesolution and extracted with ethyl acetate (50 mL×2). The combinedorganic phases were washed with water (15 mL) and brine (15 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to giveCompound 317A.

To a solution of Compound 317A (260 mg, 0.96 mmol) in THF (9 mL) wasadded LiOH H₂O (70 mg, 1.66 mmol) in water (3 mL) at −5° C., the mixturewas stirred at this temperature for 5 hours. The reaction mixture wastreated with ice water (20 mL) and extracted with ethyl acetate (50 mL).The water layer was adjusted to pH 2 with diluted HCl and extracted withethyl acetate (50 mL×2). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated.The resulting solid was washed with petroleum ether and filtered toafford the crude Compound 317B.

A mixture of Compound 317B (75 mg, (0.3 mmol), HATU (174 mg, 0.46 mmol),and Intermediate G (113 mg, 0.36 mmol) in dichloromethane (10 mL) wasstirred at room temperature overnight. The reaction mixture was treatedwith water (20 mL), extracted with dichloromethane 50 mL×2), washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated.The crude product was purified with prep-HPLC to give Compound 317.LC-MS (ESI) m/z: 539.2 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm)0.45-0.75 (m, 4H), 1.53-1.56 (m, 6H), 2.04-2.23 (m, 4H), 2.55 (d, J=4.0Hz, 3H), 3.21-3.32 (m, 2H), 3.59-3.60 (m, 1H), 3.70-3.77 (m, 4H), 4.67(d, J=10.8 Hz, 1H), 4.90 (s, 1H), 4.98 (d, J=2.8 Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 7.37 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.52(d, J=8.8 Hz, 1H), 7.76 (dd, J=1.6 Hz, 9.2 Hz, 1H), 8.36 (d, J=0.8 Hz,1H).

Example 318

To Compound 310A (1.9 g, 9.05 mmol) in DMF (15 mL) was added sodiumhydride (60% in mineral, 398 mg, 9.96 mmol) with ice bath cooling. Themixture was stirred for 30 min at room temperature and iodomethane (0.94mL, 27.15 mmol) was added. The reaction mixture was stirred at roomtemperature for 3 h, quenched with ammonium chloride solution (30 mL),and extracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with brine (200 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 0% to 90% v/v) to giveCompound 318A and Compound 318B.

A mixture of Compound 318B (225 mg, 1 mmol), Compound 175B (477 mg, 1.57mmol), Pd(PPh₃)₂Cl₂ (70 mg, 0.1 mmol), and K₂CO₃ (256 mg, 2 mmol) indioxane (5 mL) and water (0.5 mL) was stirred at 80° C. for 2 h. Themixture was cooled down and filtered. The precipitate dissolved withwater (10 mL) and purified with reverse phase chromatography usingeluent (methanol in water, from 0% to 100% v/v) to yield Compound 318C.

A mixture of Compound 318C (70 mg, 0.238 mmol), Intermediate G (74 mg,0.238 mmol), and HATU (136 mg, 0.357 mmol) in dichloromethane (2 mL) wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (100 mL), washed with water (50 mL×2) and brine (50 mL),dried over anhydrous sodium sulfate, and concentrated. The crude productwas purified with prep-HPLC to give Compound 318. LC-MS (ESI) m/z: 587[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.66-0.70 (m, 2H), 0.80-0.85(m, 2H), 1.87-1.92 (m, 2H), 2.02-2.07 (m, 2H), 2.55 (s, 3H), 3.11-3.24(m, 2H), 3.49-3.58 (m, 4H), 3.93-3.98 (m, 1H), 4.00 (s, 3H), 4.55-4.62(m, 1H), 4.89-4.90 (m, 1H), 6.06-6.07 (m, 1H), 7.35-7.46 (m, 3H),7.70-7.86 (m, 6H), 8.13 (s, 1H), 8.82 (d, J=9.6 Hz, 1H), 9.44 (brs, 1H).

Example 319

A mixture of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxane (1.07 g, 5 mmol),NBS (2.1 g, 12 mmol), and AIBN (20 mg) in CCl₄ (60 mL) was refluxedunder nitrogen for 18 h. The mixture was cooled down to room temperatureand filtered. The filtrate was washed with water (50 mL×2) and driedover anhydrous magnesium sulfate. After removal of the solvent, theresidue was dissolved in acetone (50 mL) and refluxed under nitrogen for3 h with NaI (3.75 g, 25 mmol). The mixture was cooled down to roomtemperature and evaporated. The residue was diluted with water (100 mL)and extracted with dichloromethane (50 mL×3). The organic layer waswashed with aqueous Na₂S₂O₃ solution (100 mL×2) and brine (100 mL),dried over anhydrous sodium sulfate, concentrated, and purified withflash column chromatography on silica gel (petroleum ether, 100% v/v) toyield Compound 319A.

To a solution of Compound A4 (5.7 g, 26.8 mmol) in THF (120 mL) wasadded n-BuLi (2.5 Min hexane, 14.4 mL, 36 mmol) under nitrogen at −78°C. The mixture was stirred at −78° C. for 0.5 h and a solution ofCompound 319A (3.6 g, 9 mmol) in THF (30 mL) was added. The mixture wasstirred at −78° C. for 5 min, quenched with saturated aqueous ammoniumchloride solution (100 mL), and extracted with ethyl acetate (200 mL×3).The organic layer was washed with brine (200 mL), dried over anhydroussodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 9% v/v)to furnish Compound 319B.

A mixture of Compound 319B (100 mg) in AcOH (5 mL), THF (2 mL), andwater (2 mL) was stirred at 40° C. overnight. The mixture was cooleddown to room temperature, diluted with brine (20 mL), and extracted withethyl acetate (20 mL×3). The organic layer was adjusted to pH 8 withsaturated aqueous sodium bicarbonate solution (30 mL) and separated. Theorganic layer was dried over anhydrous sodium sulfate, concentrated, andpurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, 50% v/v) to afford Compound 319C.

To a solution of Compound 319C (1.5 g, 4.2 mmol) in THF (30 mL) wasadded dropwise DIBAL-H (1.5 N in toluene, 12 mL, 17 mmol) under nitrogenat −80° C. The mixture was stirred under nitrogen at −70° C. for 0.5 h,quenched with aqueous hydrogen chloride solution (1 N, 50 mL), andextracted with ethyl acetate (50 mL×3). The organic layer was washedwith brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 55% v/v) to give Compound 319D.

To a solution of Compound 319D (1.48 g, 4 mmol) and triethylamine (1.2g, 12 mmol) in THF (30 mL) was added dropwise MsCl (0.52 g, 4.6 mmol)under nitrogen at −20° C. The mixture was stirred under nitrogen at −15°C. for 1 h, quenched with water (100 mL), and extracted with ethylacetate (50 mL×3). The organic layer was washed with brine (50 mL),dried over anhydrous sodium sulfate, and concentrated to furnishCompound 319E.

To a solution of Compound 319E (1.74 g, 4 mmol) in THF (50 mL) was addedpyrrolidine (2.8 g, 40 mmol). The mixture was stirred at 50° C.overnight. The mixture was cooled down to room temperature, diluted withwater (100 mL), and extracted with ethyl acetate (50 mL×3). The organiclayer was washed with brine (100 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with flash column chromatography onsilica gel (methanol in dichloromethane, 5% v/v) to afford Compound319F.

To a solution of Compound 319F (550 mg, 1.34 mmol) in ethanol (20 mL)was added a solution of LiOH H₂O (225 mg, 5.37 mmol) in water (5 mL).The mixture was stirred at 100° C. overnight. After removal of ethanol,the mixture was diluted with water (30 mL) and extracted with ethylacetate (30 mL×3). The organic layer was washed with brine (100 mL),dried over anhydrous sodium sulfate, and concentrated to furnishCompound 319G.

A mixture of Compound 319G (100 mg, 0.36 mmol), Compound 133D (88 mg,0.36 mmol), and HATU (275 mg, 0.72 mmol) in DMF (3 mL) was stirred atroom temperature overnight. The mixture was directly purified withprep-HPLC to yield Compound 319. LC-MS (ESI) m/z: 503 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 1.86-1.93 (m, 2H), 2.02-2.03 (m, 2H),3.10-3.22 (m, 2H), 3.44-3.47 (m, 2H), 3.53-3.56 (m, 2H), 4.47-4.54 (m,1H), 4.76 (s, 1H), 5.99 (s, 1H), 6.19 (d, J=4.0 Hz, 1H), 6.22 (d, J=3.6Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.89-6.92 (m,1H), 7.35-7.40 (m, 2H), 7.82-7.90 (m, 6H), 8.79 (d, J=10.0 Hz, 1H), 9.34(s, 1H).

Example 320

To a solution of 2-chlorobenzenethiol (7.2 g, 50 mmol) in DMSO (20 mL)was added potassium tert-butoxide (6.7 g, 60 mmol) in portions undernitrogen at 5° C. The reaction mixture was stirred at 25° C. for 15 min.To the above solution was added bromocyclopropane (12 g, 100 mmol) inDMSO (10 mL) dropwise. The reaction mixture was stirred under nitrogenat 80° C. After the reaction mixture was cooled to ambient temperature,the dark solution was diluted with water (400 mL) and extracted with amixture of ethyl acetate (60 mL×3). The combined organic phases werewashed with brine (50 mL×2), dried over anhydrous sodium sulfate,filtered, and concentrated to afford the crude product as a brown oil.The crude product was purified with flash column chromatography onsilica gel (petroleum ether) to furnish Compound 320A.

To a solution of Compound 320A (36 g, 195.6 mmol) in dry dichloromethane(600 mL) was added Br₂ (37.6 g, 235 mmol) at 5° C. dropwise. Thereaction mixture was stirred at 25° C. for 22 hours. It was washed withwater (200 mL), saturated sodium thiosulfate (200 mL) and brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated toafford the crude product as a brown oil. The crude product was purifiedwith flash column chromatography on silica gel (petroleum ether) tofurnish Compound 320B.

To a solution of Compound 320B (23.6 g, 90 mmol) in dry THF (400 mL)maintained at −70° C. was added n-BuLi (2.5 Min hexane, 36.4 mL)dropwise under nitrogen atmosphere over a period of 20 minutes. Afterthe reaction mixture was stirred at −70° C. for 40 minutes, Compound A4(11.9 g, 30 mmol) dissolved in dry THF (20 mL) was added slowly to thecold solution at a rate that maintained the internal temperature between−70° C. and −50° C. After the addition was complete, the solution wasleft to stir for 1 h. The reaction mixture was quenched with saturatedammonium chloride solution (200 mL) and extracted with ethyl acetate(200 mL×3). The organic phase was washed with water (100 mL) and brine(100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish the crude Compound 320C. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 5% to 10% v/v) to furnish the pure Compound320C.

A solution of Compound 320C (7.0 g, 13.5 mmol) in a mixture oftetrahydrofuran, water, and glacial acetic acid (145 mL, 1/1/3, v/v/v)was stirred at 25° C. for 30 h. The reaction mixture was concentratedunder reduced pressure to remove excess solvent. The residue was pouredinto ice water (20 g) and adjusted to pH 7-8 with aqueous sodiumhydroxide (1 N) and saturated aqueous sodium bicarbonate solution. Themixture was extracted with ethyl acetate (60 mL×3). The combined organicphases were washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to afford the crude target compound,which was further purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 30% to 50% v/v) to giveCompound 320D.

To a solution of Compound 320D (2.4 g, 5.9 mmol) in dry THF (50 mL)maintained at −78° C. was added diisobutylaluminum hydride (1.5 Mintoluene, 16 mL) dropwise under nitrogen atmosphere over a period of 15minutes. After the reaction mixture was stirred at −70° C. for 1 h, asolution of HCl (2 N) was added to the mixture slowly. The reactionmixture was extracted with ethyl acetate (20 mL×3), dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude targetcompound, which was further purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, from 50% to 67% v/v) tofurnish Compound 320E.

To a solution of Compound 320E (1.69 g, 4.15 mmol) dissolved in THF (30mL) was added triethylamine (1.26 g, 12.5 mmol). The mixture was cooledto −30° C., and then methanesulfonyl chloride (526 mg, 4.57 mmol) wasadded dropwise over a period of 15 minutes. After the addition wascomplete, the reaction mixture was stirred at −30° C. for 1.5 h, dilutedwith water (50 mL), and extracted with ethyl acetate (50 mL×2). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to afford Compound320F, which was directly used for the next step without furtherpurification.

To a solution of Compound 320F (910 mg, 1.88 mmol) in THF (60 mL) wasadded pyrrolidine (1.33 g, 18.8 mmol). The reaction mixture was allowedto heat to 50° C. for 16 h. The mixture was diluted with water (30 mL),extracted with ethyl acetate (60 mL×2), washed with brine (20 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to furnish acrude compound. The crude product was purified with flash columnchromatography on silica gel (methanol in dichloromethane, 7% v/v) togive Compound 320G.

To a solution of Compound 320G (548 mg, 1.19 mmol) in ethanol (14 mL)and water (2 mL) was added LiOH H₂O (200 mg, 4.77 mmol). The mixture washeated to 80° C. and stirred for 16 hours. The reaction mixture wasdiluted with water (10 mL) and extracted with dichloromethane (50 mL×2).The combined organic phases were washed with water (50 mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish Compound 320H, which was directly used for the next step withoutfurther purification.

To a solution of Compound 320H (100 mg, 0.3 mmol) in dichloromethane (10mL) was added Compound 133D (56 mg, 0.23 mmol) and HATU (131 mg, 0.35mmol). The reaction mixture was stirred at 25° C. for 3 hours. Themixture was purified with prep-HPLC to yield Compound 320. LC-MS (m/z)553 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.57 (s, 2H), 1.15 (d,J=7.6 Hz, 2H), 1.88-1.90 (m, 2H), 2.04 (s, 2H), 2.24-2.26 (m, 1H),3.12-3.23 (m, 2H), 3.42-3.56 (m, 4H), 4.59-4.61 (m, 1H), 4.92 (s, 1H),6.12 (d, J=4.0 Hz, 1H), 7.36-7.46 (m, 4H), 7.61 (d, J=8.4 Hz, 1H),7.71-7.81 (m, 6H), 8.85 (d, J=10.0 Hz, 1H), 9.36 (s, 1H).

Example 321

To a solution of Compound 258A (960 mg, 4.0 mmol) in THF (30 mL) wasadded dropwise n-BuLi (1.6 mL, 2.5 Min hexane, 4.0 mmol) under nitrogenatmosphere at −60° C. The reaction mixture was stirred at the sametemperature for 30 minutes. Compound diethyl oxalate (1.75 g, 12.0 mmol)was added. The resulting mixture was stirred at −60° C. for anadditional 30 minutes. The reaction mixture was quenched with saturatedammonium chloride solution (40 mL) and extracted with ethyl acetate (50mL×2). The combined organic phases were dried over anhydrous sodiumsulfate, filtered, evaporated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to give Compound 321A.

To a solution of Compound 321A (160 mg, 0.61 mmol) in MeOH (5 mL) wasadded LiOH.H₂O (51 mg, 1.22 mmol) and water (1.0 mL). The reactionmixture was stirred at 15° C. for 4 h. The reaction mixture wasneutralized with HCl (1 N). The resulting mixture was evaporated. Theresidue was dissolved in water (5 mL). The mixture was extracted withethyl acetate (10 mL×2), dried over anhydrous sodium sulfate, filtered,and evaporated to give Compound 321B.

To a solution of Compound 321B (70 mg, 0.30 mmol) in DMF (4 mL) wasadded Intermediate G (93 mg, 0.30 mmol) and HATU (81 mg, 0.45 mmol). Thereaction mixture was stirred at 20° C. for 5 h. The mixture was purifiedwith prep-HPLC to yield Compound 321. LC-MS (m/z) 525 [M+H]⁺; ¹H-NMR(acetone-d₆, 400 MHz): δ (ppm) 0.57-0.59 (m, 1H), 0.67-0.68 (m, 1H),0.76-0.81 (m, 2H), 1.57 (d, J=6.8 Hz, 6H), 2.09-2.11 (m, 2H), 2.27 (s,2H), 3.47-3.51 (m, 2H), 3.82-3.86 (m, 2H), 3.99-4.02 (m, 3H), 4.91-4.92(m, 1H), 5.04-5.07 (m, 1H), 5.19 (s, 1H), 1.27 (m, 1H), 7.41-7.43 (m,1H), 7.50 (s, 1H), 7.69-7.71 (m, 1H), 7.93-7.96 (m, 1H), 8.12-8.14 (m,1H), 8.21 (s, 1H), 8.55 (s, 1H), 9.01 (brs, 1H).

Example 322

A mixture of Compound 318C (80 mg, 0.272 mmol), Intermediate C (81 mg,0.272 mmol), and HATU (155 mg, 0.408 mmol) in dichloromethane (2 mL) wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (100 mL), washed with water (50 mL×2) and brine (50 mL),dried over anhydrous sodium sulfate, and concentrated. The crude productwas purified with prep-HPLC to give Compound 322. LC-MS (ESI) m/z: 573[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.84-1.93 (m, 2H), 1.99-2.08(m, 2H), 2.55 (s, 3H), 3.11-3.21 (m, 2H), 3.43-3.56 (m, 4H), 4.00 (s,3H), 4.25-4.29 (m, 4H), 4.49-4.56 (m, 1H), 4.78-4.80 (m, 1H), 6.05-6.06(m, 1H), 6.77 (s, 1H), 6.83 (d, J=11.2 Hz, 1H), 7.69-7.72 (m, 1H),7.79-7.82 (m, 1H), 8.02-8.04 (m, 4H), 8.17 (s, 1H), 8.74 (d, J=10.0 Hz,1H), 9.40 (brs, 1H).

Example 323

To a solution of Compound 266B (1.6 g, 6.7 mmol) in THF (70 mL) wasadded n-BuLi (2.5 Min hexane, 3.2 mL, 8 mmol) under nitrogen at −78° C.The mixture was stirred at −78° C. for 0.5 h and diethyl oxalate (1.96g, 13.4 mmol) was added at this temperature. The mixture was stirred at−78° C. for 0.5 h, quenched with saturated aqueous ammonium chloridesolution (100 mL), and extracted with ethyl acetate (50 mL×3). Theorganic layer was washed with brine (100 mL), dried over anhydroussodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to yield Compound 323A.

To a solution of Compound 323A (259 mg, 1 mmol) in THF (10 mL) was addeda solution of LiOH H₂O (84 mg, 2 mmol) in water (3 mL). The mixture wasstirred at room temperature overnight. After removal of THF, the mixturewas acidified to pH 1 with aqueous HCl solution (1 N) and extracted withdichloromethane (20 mL). The organic layer was dried over anhydroussodium sulfate and used directly for the next step as a dichloromethanesolution.

A mixture of Compound 323B in dichloromethane solution (115 mg, 0.5mmol), Intermediate C (150 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) indichloromethane (10 mL) and DMF (3 mL) was stirred at room temperatureovernight. The mixture was concentrated and the resulting residue waspurified with prep-HPLC to yield Compound 323. LC-MS (ESI) m/z: 510[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.47 (d, J=6.8 Hz, 6H),1.87-1.90 (m, 2H), 2.01-2.03 (m, 2H), 3.09-3.21 (m, 2H), 3.37-3.43 (m,2H), 3.53-3.59 (m, 2H), 4.22-4.32 (m, 4H), 4.52-4.56 (m, 1H), 4.78-4.79(m, 1H), 4.82-4.87 (m, 1H), 6.00 (s, 1H), 6.65 (d, J=2.8 Hz, 1H), 6.77(s, 1H), 6.82 (d, J=13.2 Hz, 1H), 7.60-7.69 (m, 3H), 8.10 (s, 1H), 8.67(d, J=9.6 Hz, 1H), 9.34 (s, 1H).

Example 324

A mixture of Compound 323B in dichloromethane solution (115 mg, 0.5mmol), Intermediate G (155 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) indichloromethane (10 mL) and DMF (3 mL) was stirred at room temperatureovernight. The mixture was concentrated and the resulting residue waspurified with prep-HPLC to yield Compound 324. LC-MS (ESI) m/z: 524[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.59-0.69 (m, 2H), 0.80-0.81(m, 2H), 1.46 (d, J=6.8 Hz, 6H), 1.87-1.89 (m, 2H), 2.03 (s, 2H),3.12-3.20 (m, 2H), 3.43-3.57 (m, 4H), 3.89-3.90 (m, 1H), 4.57-4.62 (m,1H), 4.80-4.83 (m, 1H), 4.88 (s, 1H), 6.01 (d, J=4.0 Hz, 1H), 6.62 (d,J=3.2 Hz, 1H), 7.34-7.40 (m, 2H), 7.45 (s, 1H), 7.58 (s, 2H), 7.68 (d,J=3.6 Hz, 1H), 8.04 (s, 1H), 8.68 (d, J=9.2 Hz, 1H), 9.38 (s, 1H).

Example 325

To a solution of Compound 325A (1.63 g, 10.0 mmol) and ethyl2-chloro-2-oxoacetate (1.49 g, 11.0 mmol) in dichloromethane (50 mL) wasadded dropwise titanium chloride solution (1 Min dichloromethane, 20 mL,20.0 mmol) at −10° C. The mixture was stirred for 4 hours while keepingthe temperature at −10° C. The mixture was poured into ice water, andthen extracted with diethyl ether (50 mL×3). The resulting product wasconcentrated under reduced pressure and purified with silica gel columnchromatography (ethyl acetate in petroleum ether, 30% v/v) to giveCompound 325B.

To a solution of Compound 325B (263 mg, 1.00 mmol) in MeOH (5 mL) wasadded LiOH.H₂O (63 mg, 1.50 mmol) and water (1.0 mL). The reactionmixture was stirred at 15° C. for 4 h. The reaction mixture wasneutralized with HCl (1 N). The resulting mixture was evaporated. Theresidue was dissolved in water (5 mL). The mixture was extracted withethyl acetate (10 mL×2), dried over anhydrous sodium sulfate, filtered,and evaporated to give Compound 325C.

To a solution of Compound 325C (71 mg, 0.31 mmol) in DMF (4 mL) wasadded Intermediate C (92 mg, 0.31 mmol) and HATU (81 mg, 0.45 mmol). Thereaction mixture was stirred at 20° C. for 5 h. The mixture was purifiedwith prep-HPLC to yield Compound 325. LC-MS (m/z) 514 [M+H]⁺; ¹H-NMR(acetone-d₆, 400 MHz): δ (ppm) 2.06-2.12 (m, 2H), 2.26-2.28 (m, 2H),3.55-3.64 (m, 5H), 3.82-3.85 (m, 1H), 3.93-4.10 (m, 7H), 4.23-4.31 (m,5H), 4.80-4.87 (m, 1H), 5.05-5.06 (m, 1H), 6.78-6.84 (m, 2H), 7.33-7.34(m, 2H), 8.04-8.06 (m, 1H), 8.11-8.14 (m, 2H), 8.56 (brs, 1H).

Example 326

To a solution of Compound G7 (3.8 g, 8.6 mmol) in dichloromethane (20mL) was added dropwise SOCl₂ (3.05 g, 25.7 mmol) under nitrogen at 0° C.The resulting mixture was stirred at room temperature for 2 h. Themixture was adjusted to pH 8 with sat. sodium bicarbonate solution,extracted with dichloromethane (50 mL×2), washed with brine (50 mL),dried over anhydrous sodium sulfate, concentrated, and purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, 50% v/v) to furnish Compound 326A.

To a solution of Compound 326A (600 mg, 1.30 mmol) in methanol (20 mL)was added K₂CO₃ (89 mg, 0.65 mmol) and Pt/C (60 mg). The resultingmixture was stirred under H₂ at 25° C. for 12 h. The mixture wasfiltered. The filtrate was concentrated and the resulting residue waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, 50% v/v) to furnish Compound 326B.

To a solution of Compound 326B (288 mg, 0.67 mmol) in dichloromethane(15 mL) was added PdCl₂ (30 mg). The resulting mixture was stirred underH₂ at room temperature for 12 h. The mixture was filtered. The filtratewas treated with water (20 mL) and NH₃.H₂O (20 mL). The mixture wasstirred at room temperature for 10 min, extracted with dichloromethane(50 mL×2), washed with brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated to afford Compound 326C.

A mixture of Compound 326C (90 mg, 0.3 mmol), Intermediate C (75 mg, 0.3mmol), and HATU (170 mg, 0.47 mmol) in dichloromethane (20 mL) wasstirred at room temperature for 4 h. The mixture was treated with water(50 mL), extracted with dichloromethane (20 mL×2), washed with water (20mL×3) and brine (50 mL), dried over anhydrous sodium sulfate,concentrated, and purified with prep-HPLC to furnish Compound 326. LC-MS(ESI) m/z: 521 [M+H]⁺; ¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.73-0.75 (m,4H), 2.07 (s, 4H), 2.85-3.05 (m, 4H), 3.19-3.24 (m, 1H), 3.66-3.77 (m,3H), 3.91 (s, 1H), 4.67 (s, 1H), 7.09-7.11 (m, 3H), 7.14-7.16 (m, 1H),7.18-7.24 (m, 1H), 7.50-7.54 (m, 4H), 7.85 (d, J=9.2 Hz, 1H), 7.95 (d,J=8.4 Hz, 2H), 8.94 (s, 1H).

Example 327

A mixture of Compound 273C (90 mg, 0.41 mmol), HATU (234 mg, 0.62 mmol),and Intermediate I (121 mg, 0.41 mmol) in DMF (3 mL) was stirred at 25°C. for 16 h. The mixture was diluted with ethyl acetate (30 mL), washedwith water (10 mL×2) and brine (10 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with prep-HPLC to furnish Compound327. LC-MS (ESI) m/z: 498 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)0.67-0.68 (m, 2H), 0.82-0.84 (m, 2H), 1.97-2.00 (m, 4H), 2.25-2.30 (m,1H), 2.38-2.46 (m, 1H), 3.47-4.19 (m, 11H), 4.35-4.40 (m, 1H), 4.79 (s,1H), 5.96 (s, 1H), 6.49 (d, J=8.8 Hz, 2H), 7.28-7.31 (m, 1H), 7.38-7.40(m, 2H), 7.56 (d, J=8.8 Hz, 2H), 8.47 (d, J=9.6 Hz, 1H), 9.62 (s, 1H).

Example 328

To a mixture of Compound 328A (2.4 g, 10 mmol), 3,3-diethoxyprop-1-ene(4 g, 30 mmol), and TBAC (2.7 g, 10 mmol) in DMF (80 mL) was addedPd(OAc)₂ (224 mg, 1 mmol). The reaction mixture was stirred undernitrogen at 90° C. overnight. After the completion of reaction, theresulting mixture was cooled down to room temperature, washed with brine(100 mL), dried over anhydrous sodium sulfate, and concentrated to givea residue. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 10%to 50% v/v) to furnish Compound 328B.

To a solution of Compound 328B (2.64 g, 10 mmol) in anhydrous THF (30mL) was added lithium aluminum hydride (458 mg, 12 mmol) in portionsunder nitrogen at 0° C. The mixture was stirred at room temperature for0.5 h and quenched with addition of water (2 mL). The resultingprecipitation was filtered. The filtrate was dried over anhydrous sodiumsulfate and evaporated to dryness in vacuo to afford Compound 328C.

To a solution of Compound 328C (2.2 g, 0.01 mol) in dichloromethane (40mL) was Dess-Martin periodinane (845 mg, 0.02 mol). After 4 hours, thereaction mixture was washed with brine (50 mL), dried over anhydroussodium sulfate, and concentrated to furnish a residue. The crude productwas purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, from 10% to 50% v/v) to yield Compound 328D.

To a suspension of Compound 328D (218 mg, 1 mmol) and NaCN (74 mg, 1.5mmol) in methanol (5 mL) was carefully added dropwise AcOH (1 mL). Thereaction mixture was stirred at room temperature overnight. Afterremoval of methanol, the residue was dissolved in dichloromethane (40mL), washed with brine (30 mL), dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 10%to 50% v/v) to furnish Compound 328E.

A solution of Compound 328E (2.5 g, 10 mmol) in methanol (50 mL) wasstirred under HCl gas at room temperature for 6 h. The reaction mixturewas quenched with water (30 mL) and stirred at room temperature for 1 h.After removal of solvent, the residue was dissolved in ethyl acetate(200 mL), washed with brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated to give Compound 328F.

A solution of Compound 328F (2.9 g, 10 mmol) and Dess-Martin periodinane(6.3 g, 15 mmol) in dichloromethane (50 mL) was stirred at roomtemperature for 2 h. After the completion of reaction, the reactionmixture was washed with brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated to give a residue. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 20% to 30% v/v) to afford Compound 328G.

To a solution of Compound 328G (2.9 g, 10 mmol) in dichloromethane (50mL) was added DAST (3 mL, 41.3 mmol) at room temperature. The mixturewas stirred at room temperature overnight. After the completion of thereaction, the reaction mixture was washed with water (50 mL×3) and brine(50 mL), dried over anhydrous sodium sulfate, and concentrated to afforda residue. The crude product was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 20%to 40% v/v) to give Compound 328H.

A mixture of Compound 328H (3.1 g, 10 mmol) and LiOH H₂O (1.2 g, 28.4mmol) in ethanol/water (40 mL/4 mL) was stirred at room temperatureovernight. After the completion of the reaction, the reaction mixturewas adjusted to pH 6 with aqueous HCl solution (2 N, 1.5 mL). Afterremoval of solvent, the residue was dissolved in ethyl acetate (200 mL),washed with water (50 mL×3) and brine (50 mL), dried over anhydroussodium sulfate, and concentrated to furnish Compound 3281.

To a mixture of Compound 3281 (142 mg, 0.5 mmol) and Intermediate G (232mg, 0.75 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight and theresulting solution was diluted with ethyl acetate (30 mL). The organiclayer was washed with brine (30 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified withreverse phase chromatography using eluent (methanol in water, from 10%to 55% v/v) to furnish Compound 328. LC-MS (ESI) m/z: 577 [M+H]⁺; ¹H-NMR(CD₃OD, 400 MHz): δ (ppm) 0.28-0.29 (m, 2H), 0.41-0.51 (m, 2H),2.01-2.23 (m, 6H), 2.39-2.65 (m, 2H), 3.18-3.35 (m, 3H), 3.51-3.59 (m,1H), 3.63-3.84 (m, 3H), 3.61-3.65 (m, 1H), 4.94 (s, 1H), 7.19-7.21 (m,1H), 7.31-7.38 (m, 2H), 7.42-7.51 (m, 2H), 7.61 (s, 1H), 7.76-7.89 (m,3H).

Example 329

To a solution of Compound 329A (19.8 g, 85.4 mmol) in dry THF (600 mL)maintained at −70° C. was added n-BuLi (2.5 Min hexane, 34.5 mL)dropwise under nitrogen atmosphere over a period of 20 minutes. Afterthe reaction mixture was stirred at −70° C. for 40 minutes, Compound A4(12 g, 30.4 mmol) dissolved in dry THF (50 mL) was added slowly to thecold solution at a rate that maintained the internal temperature between−70° C. and −50° C. After the addition was complete, the solution wasleft to stir for 1 h. The reaction mixture was quenched with saturatedammonium chloride solution (400 mL) and extracted with ethyl acetate(300 mL×3). The organic phase was washed with water (200 mL) and brine(200 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish the crude Compound 329B. The crude product waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 5% to 10% v/v) to furnish Compound 329B.

A solution of Compound 329B (7.4 g, 15.1 mmol) in a mixture oftetrahydrofuran, water, and glacial acetic acid (153 mL, 1/1/3, v/v/v)was stirred at 25° C. for 30 h. The reaction mixture was concentratedunder reduced pressure to remove excess solvent. The residue was pouredinto ice water (20 g) and adjusted to pH 7-8 with aqueous sodiumhydroxide (1 N) and saturated aqueous sodium bicarbonate solution. Themixture was extracted with ethyl acetate (60 mL×3). The combined organicphases were washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to afford the crude target compound,which was further purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 30% to 50% v/v) to giveCompound 329C.

To a solution of Compound 329C (3.0 g, 8 mmol) in dry THF (140 mL)maintained at −78° C. was added diisobutylaluminum hydride (1.5 Mintoluene, 25 mL) dropwise under nitrogen atmosphere over a period of 15minutes. After the reaction mixture was stirred at −70° C. for 1 h, asolution of HCl (2 N, 40 mL) was added to the mixture slowly. Thereaction mixture was extracted with ethyl acetate (30 mL×3), dried overanhydrous sodium sulfate, filtered, and concentrated to afford the crudetarget compound, which was further purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 50%to 150% v/v) to furnish Compound 329D.

To a solution of Compound 329D (2.30 g, 6.10 mmol) dissolved in THF (100mL) was added triethylamine (1.90 g, 18.81 mmol). The mixture was cooledto −30° C., and then methanesulfonyl chloride (0.80 g, 6.98 mmol) wasadded dropwise over a period of 15 minutes. After the addition wascomplete, the reaction mixture was stirred at −30° C. for 1.5 h, dilutedwith water (100 mL), and extracted with ethyl acetate (100 mL×2). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to afford Compound329E, which was directly used for the next step without furtherpurification.

To a solution of Compound 329E (3.81 g, 6.10 mmol) in THF (100 mL) wasadded pyrrolidine (11 g, 154 mmol). The reaction mixture was allowed toheat to 50° C. for 16 h. The mixture was diluted with water (100 mL),extracted with ethyl acetate (150 mL×2), washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish a crude compound. The crude product was purified with flashcolumn chromatography on silica gel (methanol in dichloromethane, 5%v/v) to give Compound 329F.

To a solution of Compound 329F (1.33 g, 3.08 mmol) in ethanol (30 mL)and water (7 mL) was added LiOH.H₂O (570 mg, 13.51 mmol). The mixturewas heated to 80° C. and stirred for 16 h. The reaction mixture wasdiluted with water (50 mL) and extracted with dichloromethane (50 mL×2).The combined organic phases were washed with water (50 mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish Compound 329G, which was directly used for the next step withoutfurther purification.

A mixture of Intermediate C (80 mg, 0.32 mmol), Compound 329G (116 mg,0.39 mmol), and HATU (187 mg, 0.49 mmol) in dichloromethane (20 mL) wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (100 mL), washed with water (50 mL×2) and brine (50 mL),dried over anhydrous sodium sulfate, and concentrated. The crude productwas purified with prep-HPLC to give Compound 329. LC-MS (ESI) m/z: 523[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 2.05-2.23 (m, 4H), 3.20-3.37(m, 2H), 3.60-3.77 (m, 4H), 4.48-4.50 (m, 1H), 4.68-4.74 (m, 2H), 5.04(s, 1H), 6.73-6.78 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.22-7.27 (m, 2H),7.42 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.65-7.76 (m,6H).

Example 330

To a solution of 4-bromo-1H-pyrazole (2.92 g, 20.0 mmol) in anhydrousDMF (50 mL) was added 2-bromopropane (3.69 g, 30.0 mmol) and potassiumcarbonate (6.90 g, 50 mmol) at room temperature. The reaction mixturewas stirred for 10 h. The mixture was diluted with water (100 mL) andextracted with ethyl acetate (150 mL×3). The combined organic extractswere washed with brine (150 mL×2) and dried over anhydrous sodiumsulfate. After filtration, the solvent was removed in vacuo and theresidue was purified with flash column chromatography on silica gel togive Compound 330A.

To a solution of Compound 330A (189 mg, 1.0 mmol) in 1,4-dioxane (10 mL)was added Intermediate 175B (304 mg, 1.0 mmol), Pd(dppf)Cl₂ (35 mg, 0.05mmol), sodium carbonate (318 mg, 3.0 mmol), and water (1 mL) undernitrogen. The reaction mixture was stirred at 110° C. for 2 hours. Theresulting mixture was cooled to 25° C. The precipitated solid wasfiltered and dried to afford Compound 330B.

To a solution of Compound 330B (25 mg, 0.10 mmol) in DMF (2 mL) wasadded Intermediate C (30 mg, 0.10 mmol) and HATU (57 mg, 0.15 mmol). Thereaction mixture was stirred at 20° C. for 2 h. The mixture was purifiedwith prep-HPLC to yield Compound 330. LC-MS (ESI) m/z: 537 [M+H]⁺;¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 1.61 (d, J=6.4 Hz, 6H), 2.09-2.12(m, 1H), 2.25-2.31 (m, 2H), 2.86 (s, 1H), 3.03 (s, 1H), 3.46-3.54 (m,2H), 3.82-3.85 (m, 1H), 3.95-4.07 (m, 3H), 4.24-4.30 (m, 4H), 5.07-5.08(m, 1H), 6.81-6.87 (m, 2H), 7.79-7.81 (m, 2H), 8.06-8.10 (m, 3H), 8.30(s, 1H), 8.56 (s, 1H), 8.69 (brs, 1H).

Example 331

To a solution of 6-bromo-1H-indole (6 g, 30 mmol) in DMF (150 mL) wasadded sodium hydride (60% suspend in oil, 2.4 g, 60 mmol) at 0° C. Themixture was stirred at 0° C. for 0.5 h and 2-iodopropane (7.6 g, 45mmol) was added at 0° C. The resultant mixture was stirred at roomtemperature overnight and diluted with ethyl acetate (300 mL). Theorganic layer was washed with water (100 mL×3) and brine (100 mL), driedover anhydrous sodium sulfate, concentrated, and purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,10% v/v) to give Compound 331A.

To a solution of Compound 331A (476 mg, 2 mmol) in THF (20 mL) was addedn-BuLi (2.5 Min hexane, 1 mL, 2.4 mmol) under nitrogen at −78° C. Themixture was stirred at −78° C. for 0.5 h and diethyl oxalate (584 mg, 4mmol) was added at −78° C. The mixture was stirred at −78° C. for 0.5 h,quenched with saturated aqueous ammonium chloride solution (50 mL), andextracted with ethyl acetate (50 mL×3). The organic layer was washedwith brine (100 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 10% v/v) to yield Compound 331B.

To a solution of Compound 331B (368 mg, 1.42 mmol) in THF (10 mL) wasadded a solution of LiOH H₂O (120 mg, 2.84 mmol) in water (3 mL). Themixture was stirred at room temperature overnight. After removal of THF,the mixture was acidified to pH 1 with aqueous HCl solution (1 N) andextracted with dichloromethane (20 mL). The organic layer was dried overanhydrous sodium sulfate and used directly for the next step as adichloromethane solution.

A mixture of Compound 331C in dichloromethane solution (115 mg, 0.5mmol), Intermediate C (150 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) indichloromethane (10 mL) and DMF (3 mL) was stirred at room temperatureovernight. The mixture was concentrated and the resulting residue waspurified with prep-HPLC to yield Compound 331. LC-MS (ESI) m/z: 510[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.46 (d, J=6.8 Hz, 3H), 1.50(d, J=6.4 Hz, 3H), 1.85-1.88 (m, 2H), 2.02-2.03 (m, 2H), 3.09-3.20 (m,2H), 3.41-3.44 (m, 2H), 3.52-3.56 (m, 2H), 4.23-4.25 (m, 4H), 4.50-4.55(m, 1H), 4.76-4.81 (m, 2H), 6.02 (s, 1H), 6.60 (d, J=3.2 Hz, 1H), 6.76(s, 1H), 6.82-6.85 (m, 1H), 7.45-7.47 (m, 1H), 7.61 (d, J=8.4 Hz, 1H),7.85 (d, J=3.2 Hz, 1H), 8.27 (s, 1H), 8.66 (d, J=9.2 Hz, 1H), 9.33 (s,1H).

Example 332

A mixture of Compound 331C in dichloromethane solution (115 mg, 0.5mmol), Intermediate G (155 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) indichloromethane (10 mL) and DMF (3 mL) was stirred at room temperatureovernight. The mixture was concentrated and the resulting residue waspurified with prep-HPLC to yield Compound 332. LC-MS (ESI) m/z: 524[M+H]⁺; 1H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.62-0.65 (m, 2H), 0.79-0.81(m, 2H), 1.45 (d, J=6.8 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 1.86-1.88 (m,2H), 2.00-2.03 (m, 2H), 3.12-3.20 (m, 2H), 3.45-3.47 (m, 4H), 3.87-3.90(m, 1H), 4.54-4.58 (m, 1H), 4.74-4.80 (m, 1H), 4.85 (s, 1H), 6.05 (s,1H), 6.59 (d, J=3.2 Hz, 1H), 7.32-7.38 (m, 2H), 7.41-7.45 (m, 2H), 7.58(d, J=8.8 Hz, 1H), 7.84 (d, J=3.2 Hz, 1H), 8.24 (s, 1H), 8.67 (d, J=9.2Hz, 1H), 9.39 (s, 1H).

Example 333

To a solution of Intermediate X (80 mg, 0.29 mmol) in a mixture ofdichloromethane (3 mL) and DMF (3 mL) was added Compound 133D (72 mg,0.29 mmol) and HATU (165 mg, 0.43 mmol). The mixture was stirred at roomtemperature for 4 h. The reaction mixture was concentrated and theresulting residue was purified with prep-HPLC to furnish Compound 333.LC-MS (ESI) m/z: 503 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.64-0.65(m, 2H), 0.74-0.77 (m, 2H), 1.29 (s, 1H), 2.02-2.07 (m, 2H), 2.17-2.21(m, 2H), 3.23-3.26 (m, 1H), 3.56 (dd, J=13.3, 2.8 Hz, 1H), 3.67-3.80 (m,3H), 3.81-3.83 (m, 1H), 4.66-4.70 (m, 1H), 4.98 (d, J=3.1 Hz, 1H), 7.04(d, J=8.7 Hz, 2H), 7.22-7.26 (m, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.68 (d,J=8.5 Hz, 2H), 7.71-7.75 (m, 2H), 7.78 (d, J=8.5 Hz, 2H).

Example 334

To a solution of 1-(4-bromo-2-fluorophenyl)ethan-1-one (1.0 g, 3.89mmol) in 1,2-ethanediol (12 mL) was added 80% of hydrazine monohydrate(0.6 mL, 7.78 mmol) at room temperature. The reaction mixture wasstirred at 200° C. in a microwave for 4.5 h, cooled down to roomtemperature, and quenched with water (50 mL). The solid precipitated wasfiltered, washed with water (20 mL), and dried under vacuo to affordCompound 334A.

To Compound 334A (1.9 g, 9.05 mmol) in DMF (15 mL) was added sodiumhydride (60% in mineral, 398 mg, 9.96 mmol) with ice bath cooling. Themixture was stirred at room temperature for 30 min and 2-iodopropane(2.7 mL, 27.15 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 h, quenched with ammonium chloride solution (30 mL),and extracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with brine (200 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 0% to 20% v/v) to giveCompound 334B and Compound 334C.

A mixture of Compound 334C (400 mg, 1.59 mmol), Compound 175B (483 mg,1.59 mmol), Pd(dppf)Cl₂ (65 mg, 0.08 mmol), and K₂CO₃ (658 mg, 4.77mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled down to roomtemperature and filtered through celite. The filtrate was diluted withwater (100 mL) and extracted with ethyl acetate (100 mL×2). The aqueouslayer was acidified to pH 3 with aqueous HCl solution (1 N) andextracted with dichloromethane (100 mL×3). The combined organic layerswere washed with water (50 mL), dried over anhydrous sodium sulfate, andconcentrated to yield Compound 334D.

A mixture of Compound 334D (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol),and Intermediate G (78 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 334. LC-MS (ESI) m/z: 615 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 0.65-0.85 (m, 4H), 1.48-1.51 (m, 6H), 1.89-2.08 (m, 4H), 2.53 (s,3H), 3.14-3.25 (m, 2H), 3.45-3.49 (m, 4H), 3.94-3.97 (m, 1H), 4.57-4.62(m, 1H), 4.92 (s, 1H), 5.03-5.09 (m, 1H), 6.10 (brs, 1H), 7.37-7.49 (m,4H), 7.77 (d, J=8.4 Hz, 2H), 7.81 (d, J=5.6 Hz, 1H), 7.88 (d, J=8.8 Hz,2H), 8.01 (s, 1H), 8.86 (d, J=10.0 Hz, 1H), 9.57 (brs, 1H).

Example 335

A mixture of Compound 334B (460 mg, 1.82 mmol), Compound 175B (553 mg,1.82 mmol), Pd(dppf)Cl₂ (73 mg, 0.09 mmol), and K₂CO₃ (753 mg, 5.46mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled down to roomtemperature and filtered through celite. The filtrate was diluted withwater (100 mL) and extracted with ethyl acetate (100 mL×2). The aqueouslayer was acidified to pH 3 with aqueous HCl solution (1 N) andextracted with dichloromethane (100 mL×3). The combined organic layerswere washed with water (100 mL×3), dried over anhydrous sodium sulfate,and concentrated to give Compound 335A.

A mixture of Compound 335A (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol),and Intermediate C (74 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 335. LC-MS (ESI) m/z: 601 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.52 (d, J=6.4 Hz, 6H), 1.88-2.05 (m, 4H), 2.67 (s, 3H), 3.10-3.22(m, 2H), 3.43-3.55 (m, 4H), 4.24-4.29 (m, 4H), 4.49-4.54 (m, 1H), 4.78(d, J=2.8 Hz, 1H), 4.86-4.92 (m, 1H), 5.99 (brs, 1H), 6.77 (s, 1H), 6.84(dd, J=11.6, 1.6 Hz, 1H), 7.36 (dd, J=8.8, 1.2 Hz, 1H), 7.82 (d, J=8.8Hz, 1H), 7.88-8.01 (m, 5H), 8.75 (d, J=9.6 Hz, 1H), 9.33 (brs, 1H).

Example 336

A mixture of Compound 335A (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol),and Intermediate G (78 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 336. LC-MS (ESI) m/z: 615 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 0.69-0.85 (m, 4H), 1.52 (d, J=6.8 Hz, 6H), 1.89-2.08 (m, 4H), 2.67(s, 3H), 3.11-3.24 (m, 2H), 3.45-3.57 (m, 4H), 3.93-3.97 (m, 1H),4.55-4.59 (m, 1H), 4.86-4.93 (m, 2H), 5.99 (brs, 1H), 7.36 (d, J=8.8 Hz,2H), 7.42-7.46 (m, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.80-7.85 (m, 3H), 7.95(s, 1H), 8.82 (d, J=10.0 Hz, 1H), 9.34 (brs, 1H).

Example 337

A mixture of Compound 334D (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol),and Intermediate C (74 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 337. LC-MS (ESI) m/z: 601 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.48 (d, J=6.4 Hz, 6H), 1.88-2.08 (m, 4H), 2.53 (s, 3H), 3.11-3.22(m, 2H), 3.39-3.55 (m, 4H), 4.20-4.29 (m, 4H), 4.51-4.55 (m, 1H), 4.79(d, J=2.8 Hz, 1H), 5.03-5.09 (m, 1H), 6.03 (brs, 1H), 6.78 (s, 1H), 6.84(d, J=11.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H),7.92-7.97 (m, 4H), 8.02 (s, 1H), 8.77 (d, J=9.6 Hz, 1H), 9.31 (brs, 1H).

Example 338

To a solution of Intermediate I (172 mg, 0.58 mmol) in dichloromethane(10 mL) was added Compound 242F (140 mg, 0.58 mmol) and HATU (332 mg,0.87 mmol). The mixture was stirred under nitrogen at room temperatureovernight. The resulting mixture was quenched with saturated aqueoussodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50mL×3). The combined organic phases were washed with water (5 mL) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude compound. The crude product was purifiedwith prep-HPLC to furnish Compound 338. LC-MS (ESI) m/z: 519 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.62-0.64 (m, 2H), 0.78-0.79 (m, 2H),2.22-2.28 (m, 1H), 2.33-2.42 (m, 1H), 3.30-3.31 (m, 1H), 3.86-3.90 (m,1H), 4.02-4.30 (m, 6H), 4.78 (d, J=2.4 Hz, 1H), 6.04 (s, 1H), 7.29 (dd,J=8.8, 2.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.55(dd, J=8.4, 2.0 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.30 (d, J=1.6 Hz, 1H),8.49 (s, 1H), 8.57 (d, J=10.0 Hz, 1H), 9.49 (s, 1H).

Example 339

A mixture of 1-bromo-4-isopropylbenzene (44 mg, 0.22 mmol), Compound296B (110 mg, 0.22 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 8.2μmol), sodium carbonate (47 mg, 0.44 mmol), water (0.5 mL), and1,4-dioxane (5 mL) was stirred under nitrogen atmosphere at 80° C. for 2h. After cooling, the reaction mixture was treated with water (5 mL),extracted with ethyl acetate (10 mL×3), washed with brine (5 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to afford thecrude product as a black oil. The oil was purified with prep-HPLC tofurnish Compound 339. LC-MS (ESI) m/z: 561 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.60-0.66 (m, 2H), 0.76-0.84 (m, 2H), 1.23 (d, J=7.2 Hz,6H), 1.82-1.92 (m, 2H), 1.97-2.07 (m, 2H), 2.91-3.00 (m, 1H), 3.08-3.27(m, 2H), 3.41-3.61 (m, 4H), 3.86-3.95 (m, 1H), 4.42-4.61 (m, 1H),4.85-4.91 (m, 1H), 6.04 (d, J=4.8 Hz, 1H), 7.33-7.44 (m, 5H), 7.64 (d,J=12.4 Hz, 2H), 7.69-7.80 (m, 4H), 8.77 (d, J=10.0 Hz, 1H), 9.34 (s,1H).

Example 340

To 6-bromo-3-methyl-1H-indazole (1.9 g, 9.05 mmol) in DMF (15 mL) wasadded sodium hydride (60% in mineral, 398 mg, 9.96 mmol) with ice bathcooling. The mixture was stirred for 30 min at room temperature andiodomethane (0.94 mL, 27.15 mmol) was added. The reaction mixture wasstirred at room temperature for 3 h, quenched with ammonium chloridesolution (30 mL), and extracted with ethyl acetate (100 mL×3). Thecombined organic layers were washed with brine (200 mL), dried overanhydrous sodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, from 0%to 90% v/v) to give Compound 340A and Compound 340B.

A mixture of Compound 340B (500 mg, 2.23 mmol), Compound 175B (678 mg,2.23 mmol), Pd(dppf)Cl₂ (90 mg, 0.11 mmol), and K₂CO₃ (923 mg, 6.69mmol) in dioxane (10 mL) and water (10 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was diluted with water (100 mL)and extracted with ethyl acetate (100 mL×2). The aqueous layer wasacidified to pH 3 with aqueous HCl solution (1 N) and extracted withdichloromethane (100 mL×3). The combined organic layers were washed withwater (50 mL), dried over anhydrous sodium sulfate, and concentrated togive Compound 340C.

A mixture of Compound 340C (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol),and Intermediate G (75 mg, 0.24 mmol) in DMF (5 mL) was stirred at 20°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 340. LC-MS (ESI) m/z: 587 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 0.65-0.87 (m, 4H), 1.85-2.04 (m, 4H), 2.53 (s, 3H), 3.10-3.24 (m,2H), 3.44-3.58 (m, 4H), 3.93-3.98 (m, 1H), 4.04 (s, 3H), 4.55-4.59 (m,1H), 4.89 (d, J=2.0 Hz, 1H), 6.06 (brs, 1H), 7.36 (dd, J=8.4, 2.0 Hz,1H), 7.42-7.50 (m, 3H), 7.80-7.86 (m, 3H), 7.89 (d, J=8.4 Hz, 2H), 7.96(s, 1H), 8.83 (d, J=9.6 Hz, 1H), 9.35 (brs, 1H).

Example 341

A mixture of Compound 340C (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol),and Intermediate C (71 mg, 0.24 mmol) in DMF (5 mL) was stirred at 20°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 341. LC-MS (ESI) m/z: 573 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.88-2.08 (m, 4H), 2.50 (s, 3H), 3.13-3.19 (m, 2H), 3.50-3.51 (m,4H), 4.04 (s, 3H), 4.26-4.29 (m, 4H), 4.51-4.53 (m, 1H), 4.79 (d, J=2.4Hz, 1H), 6.06 (brs, 1H), 6.78 (s, 1H), 6.84 (d, J=10.8 Hz, 1H), 7.49 (d,J=8.4 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.95-7.97 (m, 5H), 8.77 (d, J=9.6Hz, 1H), 9.31 (brs, 1H).

Example 342

A mixture of Compound 340A (500 mg, 2.23 mmol), Compound 175B (678 mg,2.23 mmol), Pd(dppf)Cl₂ (90 mg, 0.11 mmol), and K₂CO₃ (923 mg, 6.69mmol) in dioxane (10 mL) and water (10 mL) was stirred under nitrogen at100° C. for 3 h. The reaction mixture was cooled down to roomtemperature and filtered through celite. The filtrate was diluted withwater (100 mL) and extracted with ethyl acetate (100 mL×2). The aqueouslayer was acidified to pH 3 with aqueous HCl solution (1 N) andextracted with dichloromethane (100 mL×3). The combined organic layerswere washed with water (50 mL), dried over anhydrous sodium sulfate, andconcentrated to give Compound 342A.

A mixture of Compound 342A (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol),and Intermediate C (71 mg, 0.24 mmol) in DMF (5 mL) was stirred at 20°C. for 18 h. The mixture was directly purified with prep-HPLC to furnishCompound 342. LC-MS (ESI) m/z: 573 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ(ppm) 1.88-2.03 (m, 4H), 2.65 (s, 3H), 3.13-3.21 (m, 2H), 3.41-3.55 (m,4H), 4.09 (s, 3H), 4.27-4.29 (m, 4H), 4.48-4.53 (m, 1H), 4.78 (d, J=2.0Hz, 1H), 6.77 (s, 1H), 6.83 (d, J=12.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H),7.82-7.93 (m, 6H), 7.76 (d, J=9.6 Hz, 1H), 9.29 (brs, 1H).

Example 343

A mixture of Compound 273C (90 mg, 0.41 mmol), HATU (234 mg, 0.62 mmol),and Intermediate G (127 mg, 0.41 mmol) in DMF (3 mL) was stirred at 25°C. for 16 h. The mixture was diluted with ethyl acetate (30 mL), washedwith water (10 mL×2) and brine (10 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with prep-HPLC to furnish Compound343. LC-MS (ESI) m/z: 512 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)0.65-0.67 (m, 2H), 0.82-0.83 (m, 2H), 1.85-1.87 (m, 2H), 1.97-2.01 (m,6H), 3.09-3.20 (m, 2H), 3.48-3.54 (m, 8H), 3.89-3.94 (m, 1H), 4.50-4.55(m, 1H), 4.84 (d, J=2.4 Hz, 1H), 5.97-6.04 (m, 1H), 6.51 (d, J=9.2 Hz,2H), 7.30-7.32 (m, 1H), 7.37-7.41 (m, 2H), 7.64 (d, J=9.2 Hz, 2H), 8.47(d, J=9.6 Hz, 1H), 9.32 (s, 1H).

Example 344

To a mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (21.8 g, 100 mol)and K₂CO₃ (110 g, 800 mol) in DMF (400 mL) was added 2-iodopropane (20mL, 200 mol). The mixture was stirred at 70° C. for 4 h. It was cooledto room temperature and filtered. The cake was washed with ethyl acetate(50 mL). The filtrate was diluted with water (900 mL) and extracted withethyl acetate (400 mL×3). The organic layer was washed with water (900mL×5) and brine (900 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel on silica (ethyl acetate in petroleum, 10% v/v) to afford Compound344A.

A mixture of Compound 344A (4.3 g, 16.5 mol) and m-chloroperoxybenzoicacid (5.7 g, 33 mole) in methylene chloride (40 mL) was refluxed undernitrogen overnight. The cooled mixture was filtered and the precipitatewas washed with methylene chloride. The combined filtrate and washingwere washed with aq. sodium bicarbonate (40 mL×3) and NaCl (40 mL) andconcentrated to give a solid. The solid was dissolved in MeOH (27 mL). Asolution of 10% NaOH (9 mL) was added with cooling. After stirring for45 min at room temperature, the mixture was concentrated and 5% NaOH(100 mL) was added. The solution was washed with ether (80 mL×2). Thebasic solution was acidified with con. HCl and extracted with ether (80mL×2). The ether extracts were washed with aq. sodium bicarbonate (100mL×3), dried over MgSO₄, and concentrated to give the crude Compound344B.

To a mixture of Compound 344B (4.2 g, 17 mol) and K₂CO₃ (3.5 g, 26 mol)in DMF (60 mL) was added iodomethane (1.27 mL, 20 mol). The mixture wasstirred at 25° C. overnight. It was filtered. The cake was washed withethyl acetate (10 mL). The filtrate was diluted with water (120 mL) andextracted with ethyl acetate (40 mL×3). The organic layer was washedwith water (100 mL×5) and brine (100 mL), dried over anhydrous sodiumsulfate, concentrated, and purified with flash column chromatography onsilica gel on silica (ethyl acetate in petroleum, 5% v/v) to affordCompound 344C.

To a solution of Compound 344C (6.37 g, 24 mmol) in THF (70 mL) wasadded n-BuLi (2.4 M, 10 mL, 24 mmol) under nitrogen at −60° C. It wasstirred at −60° C. for 0.5 h. And then it was added a solution ofCompound A4 (3.21 g, 8 mmol) in THF (20 mL). The mixture was stirred at−60° C. for 0.5 h, quenched with saturated ammonium chloride solution(50 mL), extracted with ethyl acetate (60 mL×3), washed with brine (100mL), dried over anhydrous sodium sulfate, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to furnish Compound 344D.

To a solution of Compound 344D (3.89 g, 7.5 mmol) in THF (30 mL) wasadded TBAF (1 M, 2.2 mL) which had been adjusted to pH 6-7 with CH₃COOH.The mixture was stirred at 35° C. for 16 h. Water (50 mL) was added. Itwas extracted with ethyl acetate (50 mL×3). The organic layer was washedwith brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 30% v/v) to yield Compound 344E.

To a solution of Compound 344E (1.54 g, 3.70 mmol) in dry THF (35 mL)was added DIBAL-H (1.5 M, 5 mL, 7.5 mmol) slowly dropwise under nitrogenat −60° C. It was stirred at −65° C. for 0.5 h. And then DIBAL-H (1.5 M,5 mL, 7.5 mmol) was added to the reaction. It was stirred at −65° C. foranother 0.5 h. A solution of HCl (2 M) was added to quench the reaction.It was extracted with ethyl acetate (50 mL), washed with brine (40mL×2), dried over anhydrous sodium sulfate, and concentrated to yield acrude product. It was purified with flash column chromatography onsilica gel (methanol in dichloromethane, 5% v/v) to yield Compound 344F.

To a solution of Compound 344F (1.04 g, 2.56 mmol) and triethylamine(0.7 mL, 5.12 mmol) in dichloromethane (30 mL) was added MsCl (0.22 mL,2.81 mmol) at −30° C. and the resultant mixture was stirred at −30° C.for 2 h. It was treated with water (20 mL). The organic layer was washedwith water (40 mL×2) and brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated to furnish Compound 344G.

To a solution of Compound 344G (1.2 g, 2.5 mmol) in THF (20 mL) wasadded pyrrolidine (2.3 mL, 25 mmol). The mixture was stirred at 50° C.overnight. It was treated with water (20 mL), extracted with ethylacetate (10 mL×3), washed with brine (30 mL×1), dried over anhydroussodium sulfate, and concentrated in vacuo to give a crude product. Itwas purified with flash column chromatography on silica gel (methanol indichloromethane, 20% v/v) to yield Compound 344H.

To a solution of Compound 344H (840 mg, 1.8 mmol) in MeOH (30 mL) wasadded 10% Pd(OH)₂ (150 mg). The solution was stirred under H₂ atmosphereat 25° C. for 24 h. The solution was filtered. The filtrate wasconcentrated to yield the crude Compound 3441.

A mixture of Compound 3441 (72 mg, 0.22 mmol), Compound 133D (49 mg,0.20 mmol), and HATU (91 mg, 0.24 mmol) in DMF (4 mL) was stirred at 20°C. for 15 h. It was purified with prep-HPLC to give Compound 344. LC-MS(ESI) m/z: 553 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm) 1.22 (t,J=6.4 Hz, 6H), 2.08-2.17 (m, 2H), 2.25 (s, 2H), 2.49 (s, 3H), 3.74 (s,3H), 3.85 (s, 1H), 3.90-4.03 (m, 3H), 4.32-4.38 (m, 1H), 4.91 (s, 1H),5.23 (s, 1H), 6.90 (dd, J=11.2 Hz, J₂=1.6 Hz, 1H), 7.01 (s, 1H), 7.29(t, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.80-7.84 (m, 2H), 7.98 (d,J=8.4 Hz, 2H), 8.15 (d, J=10 Hz, 1H), 9.52 (brs, 1H).

Example 345

A mixture of Compound 345A (500 mg, 2.1 mmol), Pd(dppf)Cl₂ (86 mg, 0.1mmol), ethyl2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate175B (638 mg, 2.1 mmol), and K₂CO₃ (668 mg, 6.3 mmol) in 1,4-dioxane (15mL) and water (2 mL) was stirred under nitrogen at 100° C. overnight.The mixture was cooled down to room temperature, concentrated, dilutedwith water (50 mL), and extracted with ethyl acetate (30 mL×3). Theaqueous layer was acidified to pH 2 with aqueous HCl solution (1 N) andextracted with dichloromethane (10 mL×3). The dichloromethane layer wasdried over anhydrous sodium sulfate, filtered to afford Compound345B/dichloromethane solution. The solution of Compound 345B indichloromethane was directly used for the next step without furtherpurification.

To a solution of Compound 345B in dichloromethane (15 mL, from previousstep) and DMF (3 mL) was added Intermediate C (155 mg, 0.5 mmol) andHATU (380 mg, 1 mmol). The mixture was stirred at room temperatureovernight. The mixture was concentrated and the resulting residue waspurified with prep-HPLC to furnish Compound 345. LC-MS (ESI) m/z: 586[M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.49-1.51 (m, 6H), 1.88-1.89(m, 2H), 2.02-2.03 (m, 2H), 3.12-3.21 (m, 2H), 3.60-3.62 (m, 4H),4.25-4.29 (m, 4H), 4.50-4.54 (m, 1H), 4.79 (s, 1H), 4.90-4.97 (m, 1H),6.04 (s, 1H), 6.52-6.52 (m, 1H), 6.78 (s, 1H), 6.82-6.85 (m, 1H),7.43-7.45 (m, 1H), 7.61-7.62 (m, 1H), 7.66-7.68 (m, 1H), 7.88-7.94 (m,5H), 8.74-8.76 (m, 1H), 9.32 (brs, 1H).

Example 346

To a solution of Compound 346B in dichloromethane (15 mL, from theprevious step) was added Intermediate G (155 mg, 0.5 mmol) and HATU (380mg, 1 mmol). The mixture was stirred at room temperature overnight. Themixture was concentrated and the resulting residue was purified withprep-HPLC to furnish Compound 346. LC-MS (ESI) m/z: 600 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 0.68-0.70 (m, 2H), 0.82-0.83 (m, 2H),1.49-1.52 (m, 6H), 1.89-1.90 (m, 2H), 2.03-2.04 (m, 2H), 3.13-3.22 (m,2H), 3.55-3.59 (m, 4H), 3.94-3.98 (m, 1H), 4.57-4.62 (m, 1H), 4.91-4.95(m, 2H), 6.06-6.07 (m, 1H), 6.52-6.53 (m, 1H), 7.36-7.46 (m, 4H),7.62-7.73 (m, 4H), 7.84-7.86 (m, 2H), 7.92 (s, 1H), 8.82-8.84 (m, 1H),9.52 (brs, 1H).

Example 347

A mixture of Compound 342A (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol),DIPEA (0.04 mL, 0.24 mmol), and Intermediate G (75 mg, 0.24 mmol) in DMF(5 mL) was stirred at 25° C. for 2 h. The mixture was directly purifiedwith prep-HPLC to furnish Compound 347. LC-MS (ESI) m/z: 587 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.68-0.85 (m, 4H), 1.89-2.04 (m, 4H),2.65 (s, 3H), 3.11-3.24 (m, 2H), 3.47-3.57 (m, 4H), 3.92-3.97 (m, 1H),4.09 (s, 3H), 4.56-4.60 (m, 1H), 4.88 (s, 1H), 7.35-7.39 (m, 2H),7.42-7.46 (m, 2H), 7.75-7.84 (m, 5H), 7.89 (s, 1H), 8.82 (d, J=9.6 Hz,1H), 9.34 (brs, 1H).

Example 348

A mixture of Compound 3441 (72 mg, 0.22 mmol), Compound 242F (48 mg,0.20 mmol), and HATU (91 mg, 0.24 mmol) in DMF (4 mL) was stirred at 20°C. for 15 h. It was purified with prep-HPLC to give Compound 348. LC-MS(ESI) m/z: 549 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm) 1.34 (dd,J₁=15.2 Hz, J₂=10.4 Hz, 6H), 2.22 (s, 2H), 2.97 (s, 3H), 3.45 (s, 2H),3.78-3.81 (m, 4H), 3.95 (s, 3H), 4.23-4.29 (m, 1H), 4.86 (s, 1H), 5.17(s, 1H), 6.86 (dd, J₁=10.8 Hz, J₂=1.6 Hz, 1H), 6.98 (s, 1H), 7.51 (dd,J₁=8.8 Hz, J₂=2 Hz, 1H), 8.09-8.17 (m, 3H), 8.60 (s, 1H), 9.83 (brs,1H).

Example 349

A mixture of 3-(4-bromophenyl)-1H-pyrazole (1.0 g, 4.5 mmol),cyclopropylboronic acid (0.8 g, 9 mmol), Cu(OAc)₂ (1.6 g, 9 mmol),Na₂CO₃ (0.9 g, 9 mmol), bipyridine (1.4 g, 9 mmol), and 4 Å molecularsieve powder (5 g) in 1,2-dichloroethane (20 mL) was stirred at 30° C.for 72 h. After filtration, the mixture was diluted with dichloromethane(50 mL), washed with water (30 mL×2) and brine (50 mL), dried overanhydrous sodium sulfate, and concentrated to give a crude compound. Thecrude product was purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to affordCompound 349A.

To a solution of Compound 349A (342 mg, 1.3 mmol) in dry THF (10 mL) wasadded n-BuLi (2.5 N in hexane, 0.6 mL, 1.5 mmol) under nitrogen at −78°C. The resulting solution was stirred at −78° C. for 30 min andtransferred into a stirred solution of diethyl oxalate (0.97 g, 6.6mmol) in dry THF (5 mL) at this temperature. The solution was stirred at−78° C. for 1 h, quenched with addition of saturated aqueous ammoniumchloride solution (10 mL), poured into water (50 mL), and extracted withethyl acetate (50 mL×2). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated invacuo to give Compound 349B, which was used for the next step withoutfurther purification.

A mixture of Compound 349B (0.26 g, 0.9 mmol) and LiOH.H₂O (77 mg, 1.8mmol) in THF (5 mL) and water (2 mL) was stirred at 0° C. for 2 h. Themixture was diluted with ethyl acetate (30 mL), washed with water (10mL×2) and brine (10 mL), dried over anhydrous sodium sulfate,concentrated, and purified with reverse phase chromatography usingeluent (methanol in water, from 0% to 100% v/v) to afford Compound 349C.

A mixture of Compound 349D (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol),and Intermediate G (93 mg, 0.3 mmol) in dichloromethane (5 mL) wasstirred at 25° C. for 16 h. The mixture was diluted with ethyl acetate(30 mL), washed with water (10 mL×2) and brine (10 mL), dried overanhydrous sodium sulfate, and concentrated to yield a crude compound.The crude product was purified with prep-HPLC to furnish Compound 349.LC-MS (ESI) m/z: 549 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)0.69-0.71 (m, 2H), 0.83-0.84 (m, 2H), 1.01-1.03 (m, 2H), 1.11-1.12 (m,2H), 1.88-1.89 (m, 2H), 2.02-2.04 (m, 2H), 3.12-3.21 (m, 2H), 3.48-3.55(m, 4H), 3.77-3.84 (m, 1H), 3.92-3.97 (m, 1H), 4.57 (s, 1H), 4.87 (s,1H), 6.01-6.10 (m, 1H), 6.82-6.83 (m, 1H), 7.35-7.45 (m, 3H), 7.72-7.74(m, 2H), 7.87-7.91 (m, 3H), 8.77 (d, J=10 Hz, 1H), 9.32 (s, 1H).

Example 350

A mixture of Compound 349D (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol),and Intermediate C (89 mg, 0.3 mmol) in dichloromethane (5 mL) wasstirred at 25° C. for 16 h. The mixture was diluted with ethyl acetate(30 mL), washed with water (10 mL×2) and brine (10 mL), dried overanhydrous sodium sulfate, and concentrated to yield a crude compound.The crude product was purified with prep-HPLC to furnish Compound 350.LC-MS (ESI) m/z: 535 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)1.01-1.03 (m, 2H), 1.10-1.11 (m, 2H), 1.87-1.88 (m, 2H), 2.02-2.03 (m,2H), 3.10-3.20 (m, 2H), 3.43-3.45 (m, 2H), 3.53-3.56 (m, 2H), 3.78-3.83(m, 1H), 4.27-4.30 (m, 4H), 4.51-4.53 (m, 1H), 4.77 (s, 1H), 6.76-6.85(m, 3H), 7.83-7.85 (m, 2H), 7.90-7.93 (m, 3H), 8.73 (d, J=9.6 Hz, 1H),9.29 (s, 1H).

Example 351

To a solution of 3-(4-bromophenyl)-1H-pyrazole (1.0 g, 4.5 mmol) in DMF(20 mL) was added NaH (198 mg, 5 mmol). The mixture was stirred at 25°C. for 0.5 h and 2-iodopropane (1.53 g, 9 mmol) was added. The mixturewas stirred at 25° C. for 2 h. The mixture was diluted with water (30mL) and extracted with ethyl acetate (50 mL×2). The combined organiclayers were washed with brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo to give a crude compound. The crudeproduct was purified with flash column chromatography on silica gel(ethyl acetate in petroleum ether, from 0% to 10% v/v) to affordCompound 351A.

To a solution of Compound 351A (343 mg, 1.3 mmol) in dry THF (10 mL) wasadded n-BuLi (2.5 N in hexane, 0.6 mL, 1.5 mmol) under nitrogen at −78°C. The resulting solution was stirred at −78° C. for 30 min andtransferred into a stirred solution of diethyl oxalate (0.97 g, 6.6mmol) in dry THF (5 mL) at this temperature. The solution was stirred at−78° C. for 1 h, quenched with addition of saturated aqueous ammoniumchloride solution (10 mL), poured into water (50 mL), and extracted withethyl acetate (50 mL×2). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, and concentrated invacuo to give Compound 351B, which was used for the next step withoutfurther purification.

A mixture of Compound 351B (0.27 g, 0.9 mmol) and LiOH.H₂O (77 mg, 1.8mmol) in THF (5 mL) and water (2 mL) was stirred at 0° C. for 2 h. Themixture was diluted with ethyl acetate (30 mL), washed with water (10mL×2) and brine (10 mL), dried over anhydrous sodium sulfate,concentrated, and purified with reverse phase chromatography usingeluent (methanol in water, from 0% to 100% v/v) to afford Compound 351C.

A mixture of Compound 351C (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol),and Intermediate G (93 mg, 0.3 mmol) in dichloromethane (5 mL) wasstirred at 25° C. for 16 h. The mixture was diluted with ethyl acetate(30 mL), washed with water (10 mL×2) and brine (10 mL), dried overanhydrous sodium sulfate, and concentrated to yield a crude compound.The crude product was purified with prep-HPLC to furnish Compound 351.LC-MS (ESI) m/z: 551 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm)0.70-0.71 (m, 2H), 0.83-0.84 (m, 2H), 1.47 (s, 3H), 1.48 (s, 3H),1.89-1.90 (m, 2H), 2.04-2.05 (m, 2H), 3.12-3.21 (m, 2H), 3.48-3.51 (m,4H), 3.94 (s, 1H), 4.56-4.58 (m, 2H), 4.88 (s, 1H), 6.05-6.07 (m, 1H),6.82-6.83 (m, 1H), 7.35-7.45 (m, 3H), 7.71-7.73 (m, 2H), 7.88-7.90 (m,3H), 8.78 (d, J=9.2 Hz, 1H), 9.41 (s, 1H).

Example 352

A mixture of Compound 351C (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol),and Intermediate C (89 mg, 0.3 mmol) in DMF (5 mL) was stirred at 25° C.for 16 h. The mixture was diluted with ethyl acetate (30 mL), washedwith water (10 mL×2) and brine (10 mL), dried over anhydrous sodiumsulfate, and concentrated to yield a crude compound. The crude productwas purified with prep-HPLC to furnish Compound 352. LC-MS (ESI) m/z:537 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.47 (s, 3H), 1.48 (s,3H), 1.87-1.88 (m, 2H), 2.02-2.03 (m, 2H), 3.12-3.21 (m, 2H), 3.43-3.45(m, 2H), 3.54-3.56 (m, 2H), 4.27-4.30 (m, 4H), 4.52-4.58 (m, 2H), 4.78(s, 1H), 6.77-6.85 (m, 3H), 7.83-7.85 (m, 2H), 7.90-7.94 (m, 3H), 8.74(d, J=9.6 Hz, 1H), 9.29 (s, 1H).

Example 353

A mixture of 1-fluoro-4-iodobenzene (5 g, 23 mmol), 5-bromo-1H-indazole(4.4 g, 23 mmol), CuI (428 mg, 2.3 mmol), L-proline (518 mg, 4.5 mmol),and K₃PO₄ (9.55 g, 45 mmol) in 1,4-dioxane (200 mL) was stirred undernitrogen at reflux for 24 h. The resulting mixture was cooled to roomtemperature. The mixture was treated with water (200 mL), extracted withethyl acetate (100 mL×2), washed with sat. sodium bicarbonate (100 mL×2)and brine (100 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 10% v/v) to furnish Compound 353A.

To a solution of Compound 353A (650 mg, 2.2 mmol) in THF (50 mL) wasadded dropwise n-BuLi (1.1 mL, 2.7 mmol) under nitrogen at −78° C. Theresulting mixture was stirred at −78° C. for 15 min. To the resultingmixture was added diethyl oxalate (1.6 g, 11.2 mmol) as a soon as aquickly. The mixture was stirred at −78° C. for 1 h, quenched with sat.ammonium chloride solution, treated with water (50 mL), extracted withethyl acetate (50 mL×2), washed with brine (50 mL), dried over anhydroussodium sulfate, concentrated, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to furnish Compound 353B.

To a solution of Compound 353B (130 mg, 0.42 mmol) in THF (5 mL) wasadded dropwise LiOH.H₂O (35 mg, 0.83 mmol) in water (2 mL) at −20° C.The resulting mixture was stirred at −20° C. for 1 h. The mixture wasadjusted pH to 1 with diluted HCl. The resulting mixture was extractedwith ethyl acetate (50 mL×2), and then the organic layer was dried overanhydrous sodium sulfate and concentrated to furnish Compound 353C.

A mixture of Compound 353C (100 mg, 0.35 mmol), Intermediate 353G (109mg, 0.35 mmol), and HATU (210 mg, 0.53 mmol) in DMF (5 mL) was stirredat room temperature for 12 h. The mixture was treated with water (50mL), extracted with dichloromethane (20 mL×2), washed with water (20mL×3) and brine (50 mL), dried over anhydrous sodium sulfate,concentrated, and purified with prep-HPLC to furnish Compound 353. LC-MS(ESI) m/z: 577 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.59-0.81 (m,4H), 1.86-2.05 (m, 4H), 3.13-3.22 (m, 2H), 3.50-3.57 (m, 4H), 3.89-3.92(m, 1H), 4.56-4.62 (m, 1H), 4.89 (s, 1H), 6.05-6.06 (m, 1H), 7.34-7.51(m, 5H), 7.79-7.85 (m, 4H), 7.43 (s, 1H), 8.56 (s, 1H), 8.01 (d, J=9.6Hz, 1H), 9.39 (s, 1H).

Example 354

A mixture of Compound 354A (100 mg, 0.35 mmol), Intermediate G (109 mg,0.35 mmol), and HATU (210 mg, 0.53 mmol) in DMF (5 mL) was stirred atroom temperature for 12 h. The mixture was treated with water (50 mL),extracted with dichloromethane (20 mL×2), washed with water (20 mL×3)and brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with prep-HPLC to furnish Compound 354. LC-MS (ESI) m/z:577 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.61-0.79 (m, 4H),1.86-2.02 (m, 4H), 3.11-3.18 (m, 2H), 3.45-3.53 (m, 4H), 3.85-3.89 (m,1H), 4.45-4.50 (m, 1H), 4.81 (s, 1H), 6.01 (s, 1H), 6.93 (d, J=9.2 Hz,1H), 7.25-7.39 (m, 7H), 7.73-7.76 (m, 1H), 8.27-8.28 (d, J=2.0 Hz, 1H),8.63 (d, J=9.6 Hz, 1H), 9.21 (s, 1H), 9.30 (s, 1H).

Example 355

A mixture of 1-(4-bromophenyl)ethan-1-one (2.0 g, 10 mmol) intetrahydrofuran (30 mL) was maintained at −70° C., and methylmagnesiumbromide (3 M, 6.7 mL) was added at −70° C. The reaction mixture wasstirred at −78° C. for 0.5 h. The reaction mixture was treated withwater (30 mL) and extracted with ethyl acetate (50 mL×2). The combinedorganic layers were washed with brine (15 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The remaining residue waspurified with flash column chromatography on silica gel (ethyl acetatein petroleum ether, from 10% to 25% v/v) to furnish Compound 355A.

A mixture of Compound 175B (616 mg, 2 mmol), Compound 355A (428 mg, 2mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (168mg, 0.2 mol), sodium carbonate (424 mg, 4 mmol), water (0.5 mL), and1,4-dioxane (5 mL) was stirred under nitrogen atmosphere at 80° C. for 2h. After cooling, the reaction mixture was treated with water (30 mL),washed with ethyl acetate (30 mL×3), adjusted pH to 2.0 withhydrochloric acid (1 M), extracted with ethyl acetate (20 mL×3), washedwith brine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish Compound 355B.

A mixture of Compound 355B (100 mg, 0.35 mmol), Intermediate G (108 mg,0.35 mmol), and HATU (266 mg, 0.70 mmol) in DMF (3.5 mL) was stirred at25° C. for 2 h. The mixture was purified with prep-HPLC directly tofurnish Compound 355. LC-MS (ESI) m/z: 559 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 0.68-0.76 (m, 2H), 0.77-0.88 (m, 2H), 1.68-1.92 (m, 1H),2.07-2.21 (m, 2H), 2.22 (s, 3H), 2.23-2.28 (m, 1H), 3.33-3.50 (m, 2H),3.76-3.97 (m, 6H), 4.84-4.90 (m, 1H), 5.18-5.26 (m, 2H), 5.53 (s, 1H),7.28-7.43 (m, 2H), 7.45-7.57 (m, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.75-7.81(m, 4H), 7.92-8.01 (m, 2H), 8.21 (d, J=6.0 Hz, 1H), 10.84 (brs, 1H).

Example 356

A mixture of Compound 296A (150 mg, 0.54 mmol), Intermediate C (175 mg,0.59 mmol), and HATU (308 mg, 0.81 mmol) in dichloromethane (5 mL) wasstirred at 25° C. overnight. The mixture was quenched with water (10mL), extracted with dichloromethane (5 mL×2), washed with brine (5 mL),dried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude product was purified with prep-HPLC to furnish Compound 356A.

A mixture of 2-(4-bromophenyl)propan-2-ol (34 mg, 0.15 mmol), Compound356A (75 mg, 0.15 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 8.2μmol), sodium carbonate (44 mg, 0.30 mmol), water (0.5 mL), and1,4-dioxane (5 mL) was stirred under nitrogen atmosphere at 80° C. for 2h. After cooling, the reaction mixture was treated with water (5 mL),extracted with ethyl acetate (10 mL×3), washed with brine (5 mL), driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified with prep-HPLC. The solution was adjusted to pH=8.0 withsodium bicarbonate solution, extracted with ethyl acetate (50 mL×2),dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish Compound 356. LC-MS (ESI) m/z: 563 [M+H]⁺; ¹H-NMR (CDCl₃, 400MHz): δ (ppm) 1.42-1.75 (m, 6H), 1.79-1.86 (m, 4H), 2.74-2.81 (m, 4H),2.96-3.04 (m, 2H), 4.24-4.31 (m, 6H), 5.05 (d, J=2.4 Hz, 1H), 6.70-6.76(m, 2H), 7.39 (d, J=8.8 Hz, 1H), 7.75-7.64 (m, 5H), 7.68 (d, J=9.2 Hz,2H), 8.31 (d, J=8.8 Hz, 2H).

Example 357

A mixture of 1-bromo-4-isopropylbenzene (30 mg, 0.15 mmol), Compound356A (75 mg, 0.15 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 8.2μmol), sodium carbonate (32 mg, 0.30 mmol), water (0.5 mL), and1,4-dioxane (5 mL) was stirred under nitrogen atmosphere at 80° C. for 2h. After cooling, the reaction mixture was treated with water (5 mL),extracted with ethyl acetate (10 mL×3), washed with brine (5 mL), driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified with prep-HPLC to furnish Compound 357. LC-MS (ESI) m/z:547 [M+H]⁺; ¹H-NMR ((CD₃)₂CO, 400 MHz): δ (ppm) 1.64 (m, 6H), 2.08-2.11(m, 3H), 2.17-2.23 (m, 1H), 2.96-3.043 (m, 4H), 3.17-3.82 (m, 4H),4.21-4.33 (m, 3H), 4.37 (d, 1H), 4.69-5.75 (m, 2H), 6.85-7.07 (m, 2H),7.35-7.43 (m, 2H), 7.46-7.79 (m, 3H), 7.81-7.87 (m, 1H), 7.89-7.98 (m,1H), 8.02-8.14 (m, 1H).

Example 358

A mixture of 2-(4-bromophenyl)propan-2-ol (49 mg, 0.23 mmol), Compound296B (110 mg, 0.23 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.4 mg, 10μmol), potassium carbonate (49 mg, 0.46 mmol), water (1 mL), and1,4-dioxane (5 mL) was heated under nitrogen atmosphere at 100° C. for 2h. After cooling, water (5 mL) was added, and the mixture was extractedwith ethyl acetate (10 mL×3). The combined organic layers were washedwith brine (5 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated to afford the crude productas a black oil. The oil was purified with prep-HPLC. The solution wasadjusted to pH=8.0 with sodium bicarbonate solution, extracted withethyl acetate (50 mL×2), dried over anhydrous sodium sulfate, filtered,and concentrated to furnish Compound 358. LC-MS (ESI) m/z: 577 [M+H]⁺;¹H-NMR (CDCl₃, 400 MHz): δ (ppm) 0.76-0.88 (m, 4H), 1.23-1.30 (m, 1H),1.63 (s, 6H), 1.83-1.88 (m, 4H), 2.01 (s, 1H), 2.73-2.81 (m, 5H),2.97-3.03 (m, 2H), 3.74-3.79 (m, 1H), 4.33 (d, J=4.4 Hz, 1H), 5.11 (d,J=2.4 Hz, 1H), 7.21-7.28 (m, 1H), 7.35-7.51 (m, 3H), 7.57-7.63 (m, 4H),7.68 (d, J=7.2 Hz, 2H), 8.26 (d, J=8.8 Hz, 1H).

Example 359

To a stirred solution of Compound 175B (1.29 g, 4.24 mmol) in DMF (20mL) and water (20 mL) was added Na₂CO₃ (1.12 g, 10.6 mmol), Pd(PPh₃)₄(247 mg, 0.21 mmol), and 2-bromo-5-chlorothiophene (838 mg, 4.24 mmol).The mixture was stirred under nitrogen at 90° C. for 16 h. The reactionmixture was cooled to room temperature and purified with reverse phasechromatography using eluent (methanol in water (include 0.05% ofNH₃.H₂O), from 0% to 40% v/v) to afford Compound 359A.

To a solution of Intermediate S (55 mg, 0.22 mmol) in dichloromethane(10 mL) was added Compound 359A (50 mg, 0.18 mmol) and HATU (107 mg,0.28 mmol). The mixture was stirred under nitrogen at room temperatureovernight. The resulting mixture was quenched with saturated aqueoussodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50mL×3). The combined organic phases were washed with water (5 mL) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude compound. The crude product was purifiedwith prep-HPLC to furnish Compound 359. LC-MS (ESI) m/z: 543 [M+H]⁺;1H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.68-0.70 (m, 2H), 0.79-0.81 (m, 2H),1.87-1.90 (m, 2H), 2.02-2.04 (m, 2H), 3.12-3.18 (m, 2H), 3.45-3.55 (m,4H), 3.92-3.95 (m, 1H), 4.51-4.53 (m, 1H), 4.85 (d, J=2.4 Hz, 1H), 6.05(d, J=4.4 Hz, 1H), 7.19 (t, J=8.8 Hz, 2H), 7.28 (d, J=4.0 Hz, 1H), 7.39(t, J=8.8 Hz, 1H), 7.63 (d, J=4.0 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.83(d, J=8.4 Hz, 2H), 7.75 (d, J=9.6 Hz, 1H), 9.31 (s, 1H).

Example 360

To a solution of Intermediate C (100 mg, 0.34 mmol) in dichloromethane(10 mL) was added Compound 359A (75 mg, 0.28 mmol) and HATU (160 mg,0.42 mmol). The mixture was stirred under nitrogen at room temperatureovernight. The resulting mixture was quenched with saturated aqueoussodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50mL×3). The combined organic phases were washed with water (5 mL) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude compound. The crude product was purifiedwith prep-HPLC to furnish Compound 360. LC-MS (ESI) m/z: 545 [M+H]⁺;1H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.86-1.88 (m, 2H), 2.01-2.04 (m, 2H),3.11-3.18 (m, 2H), 3.52-3.54 (m, 4H), 4.28-4.29 (m, 4H), 4.48-4.50 (m,1H), 4.76 (s, 1H), 6.03 (s, 1H), 6.75 (s, 1H), 6.81 (d, J=11.6 Hz, 1H),7.27 (d, J=2.0 Hz, 1H), 7.65 (d, J=3.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H),7.87 (d, J=8.4 Hz, 2H), 8.73 (d, J=9.6 Hz, 1H), 9.28 (s, 1H).

Example 361

To a mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (21 g, 97 mol)and K₂CO₃ (20 g, 145 mmol) in DMF (200 mL) was added iodomethane (16.3g, 115 mmol). The mixture was stirred at room temperature overnight. Themixture was diluted with water (500 mL) and extracted with ethyl acetate(400 mL×3). The organic layer was washed with water (500 mL×3) and brine(200 mL), dried over anhydrous sodium sulfate, and concentrated to giveCompound 361A.

A mixture of Compound 361A (15.6 g, 66.9 mmol) and m-chloroperoxybenzoicacid (23 g, 133.9 mmol) in methylene chloride (200 mL) was stirred at40° C. overnight. The mixture was filtered and the precipitate waswashed with methylene chloride. The combined filtrate and washing werewashed with aq. sodium bicarbonate (100 mL×3) and brine (100 mL) andconcentrated to give a yellow oil. The crude Compound was dissolved inMeOH (300 mL). A solution of 33% NaOH (30 mL) was added with cooling.After stirring for 2 h at room temperature, the mixture was acidifiedwith concentrated HCl and extracted with ethyl acetate (200 mL×2). Theextract was washed with aqueous sodium bicarbonate (100 mL×3), driedover anhydrous sodium sulfate, and concentrated to give the crudeCompound 361B.

To a mixture of Compound 361B (10.3 g, 46.6 mmol) and K₂CO₃ (12.9 g,93.2 mmol) in DMF (100 mL) was added 2-bromopropane (11.5 g, 93.2 mmol).The mixture was stirred at 80° C. overnight. The mixture was dilutedwith water (500 mL) and extracted with ethyl acetate (200 mL×2). Theorganic layer was washed with water (300 mL×3) and brine (100 mL), driedover anhydrous sodium sulfate, concentrated, and purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum, 5% v/v)to give Compound 361C.

To a solution of Compound 361C (8.43 g, 32 mmol) in THF (100 mL) wasadded n-BuLi (2.4 M, 13.2 mL, 33.1 mmol) under nitrogen at −78° C. Itwas stirred at −78° C. for 10 min. A solution of Compound A4 (4.2 g,10.68 mmol) in THF (10 mL) was added. The mixture was stirred at −78° C.for 0.5 h, quenched with saturated ammonium chloride solution (50 mL),extracted with ethyl acetate (200 mL), washed with brine (100 mL), driedover anhydrous sodium sulfate, and purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to furnish Compound 361D.

A solution of Compound 361D (5 g, 9.62 mmol) in THF (25 mL), water (25mL), and acetic acid (75 mL) was stirred at 35° C. overnight. Thesolvent was removed with evaporation under reduced pressure and theresidue was diluted with water (200 mL) and extracted with ethyl acetate(200 mL). The organic layer was washed with aqueous sodium bicarbonate(100 mL) and brine (100 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 33% v/v) to yield Compound 361E.

To a solution of Compound 361E (1.6 g, 3.95 mmol) in dry THF (70 mL) wasadded DIBAL-H (1 M, 15.8 mL, 15.8 mmol) slowly dropwise under nitrogenat −78° C. It was stirred at −78° C. for 1 h. A solution of HCl (2 M, 20mL) was added to quench the reaction. It was extracted with ethylacetate (50 mL), washed with brine (40 mL), dried over anhydrous sodiumsulfate, and concentrated to yield a crude product. It was purified withflash column chromatography on silica gel (ethyl acetate in petroleumether, 50% v/v) to give Compound 361F.

To a solution of Compound 361F (1.44 g, 3.53 mmol) and triethylamine(1.07 g, 10.6 mmol) in dichloromethane (30 mL) was added MsCl (445 mg,3.89 mmol) at −30° C. and the resultant mixture was stirred at −30° C.for 1 h. It was treated with water (100 mL) and dichloromethane (100mL). The organic layer was washed with water (40 mL×2) and brine (50mL), dried over anhydrous sodium sulfate, and concentrated to furnishCompound 361G.

To a solution of Compound 361G (1.71 g, 3.6 mmol) in THF (40 mL) wasadded pyrrolidine (2.61 g, 36 mmol). The mixture was stirred at 50° C.overnight. It was treated with water (100 mL), extracted with ethylacetate (100 mL×3), washed with brine (100 mL), dried over anhydroussodium sulfate, and concentrated in vacuo to give a crude product. Itwas purified with flash column chromatography on silica gel (methanol indichloromethane, 5% v/v) to give Compound 361H.

To a solution of Compound 361H (1.25 g, 2.71 mmol) in ethanol (24 mL)was added LiOH.H₂O (456 mg, 10.86 mmol). The solution was stirred at 80°C. overnight. The mixture was diluted with ethyl acetate (100 mL),washed with water (100 mL) and brine (100 mL), dried over anhydroussodium sulfate, and concentrated to yield the crude Compound 3611.

A mixture of Compound 3611 (100 mg, 0.306 mmol), Intermediate C (69 mg,0.306 mmol), and HATU (174 mg, 0.459 mmol) in dichloromethane (2 mL) wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (50 mL), washed with water (100 mL) and brine (50 mL),dried over anhydrous sodium sulfate, concentrated, and purified withprep-HPLC to give Compound 361. LC-MS (ESI) m/z: 553 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 1.17 (d, J=6.0 Hz, 3H), 1.26 (d, J=6.0 Hz,3H), 1.87-1.93 (m, 2H), 2.01-2.05 (m, 2H), 3.11-3.24 (m, 2H), 3.45-3.57(m, 4H), 3.77 (s, 3H), 4.49-4.57 (m, 2H), 4.84-4.85 (m, 1H), 6.09 (d,J=4.0 Hz, 1H), 6.85 (d, J=11.6 Hz, 1H), 6.89 (s, 1H), 7.38 (t, J=8.8 Hz,2H), 7.78-7.87 (m, 6H), 8.77 (d, J=10.0 Hz, 1H), 9.38 (brs, 1H).

Example 362

To a mixture of Compound C3 (31 g, 150 mol) and Li₂CO₃ (22.4 g, 310 mol)in DMF (250 mL) was added 3-bromo-2-methylprop-1-ene (31.9 mL, 310 mol).The mixture was stirred at 55° C. for 48 h, cooled down to roomtemperature, and filtered. The cake was washed with ethyl acetate (100mL). The filtrate was diluted with water (500 mL) and extracted withethyl acetate (200 mL×3). The organic layer was washed with saturatedaqueous LiCl solution (100 mL×5), dried over anhydrous sodium sulfate,filtered, and concentrated. The crude product was purified with flashcolumn chromatography on silica gel on silica gel (ethyl acetate inpetroleum ether, 5% v/v) to give a mixture of Compound 362A and Compound362A′.

A solution of Compound 362A and Compound 362A′ (23 g, 88.5 mmol) informic acid (200 mL) was stirred and heated to reflux for 2 h. Afterremoval of the solvent, the residue was diluted with dichloromethane(200 mL). The mixture was carefully adjusted pH to 9 with saturatedaqueous sodium bicarbonate solution at 0° C. and extracted withdichloromethane (100 mL×3). The combined organic phases were washed withwater (50 mL×2) and brine (50 mL×2), dried over anhydrous sodiumsulfate, filtered, and concentrated to afford a crude compound. Thecrude product was purified with flash column chromatography on silicagel (ethyl acetate in petroleum ether, 10% v/v) to furnish a mixture ofCompound 362B and Compound 362B′.

To a solution of Compound 362B and Compound 362B′ (3.8 g, 14.6 mmol) indry THF (80 mL) maintained at −60° C. was dropwise added n-BuLi (2.5 Minhexane, 6.0 mL, 15.1 mmol) under nitrogen atmosphere over a period of 20minutes. After the reaction mixture was stirred at −60° C. for 40minutes, a solution of Compound A4 (1.93 g, 4.87 mmol) in dry THF (20mL) was added slowly. After the completion of addition, the solution wasleft to stir for 0.5 h at −60° C. The reaction mixture was quenched withsaturated aqueous ammonium chloride solution (20 mL) and extracted withethyl acetate (100 mL×3). The organic phase was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated tofurnish a crude compound. The crude product was purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 5% to 10% v/v) to yield Compound 362C.

A solution of Compound 362C (1.1 g, 2.13 mmol) in a mixture oftetrahydrofuran, water, and glacial acetic acid (25 mL, 1/1/3 v/v/v) wasstirred at 35° C. for 16 h. The reaction mixture was concentrated underreduced pressure to remove excess solvent. The residue was poured intoethyl acetate (50 mL) and water (20 mL). The mixture was adjusted to pH7˜8 with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (100 mL×3). The combined organic phases were washedwith brine (10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford the crude target compound. The crude product wasfurther purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 50% v/v) to give Compound 362D.

To a solution of Compound 362D (690 mg, 1.71 mmol) in dry THF (20 mL)maintained at −78° C. was added diisobutylaluminum hydride (1.0 Mintoluene, 6.85 mL) dropwise under nitrogen atmosphere over a period of 15minutes. After the reaction mixture was stirred at −70° C. for 1 h,saturated solution of ammonium chloride solution (10 mL) was added tothe mixture slowly. The reaction mixture was extracted with ethylacetate (50 mL×3), washed with water (10 mL) and brine (10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to afford thecrude target compound. The crude product was further purified with flashcolumn chromatography on silica gel (ethyl acetate in petroleum ether,from 50% to 87% v/v) to furnish Compound 362E.

To a solution of Compound 362E (600 mg, 1.48 mmol) dissolved in dry THF(15 mL) was added triethylamine (0.62 mL, 4.44 mmol). The mixture wascooled to −40° C., and then methanesulfonyl chloride (0.17 mL, 2.22mmol) was added dropwise. After the addition was complete, the reactionmixture was stirred at −40° C. for 2 h, diluted with water (30 mL), andextracted with ethyl acetate (30 mL×2). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford a crude compound. The crude productwas purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 50% v/v) to give Compound 362F.

To a solution of Compound 362F (320 mg, 0.66 mmol) in THF (10 mL) wasadded pyrrolidine (0.55 mL, 6.6 mmol). The reaction mixture was allowedto heat to 50° C. for 16 h. The mixture was diluted with water (10 mL),extracted with ethyl acetate (50 mL×3), washed with water (10 mL) andbrine (10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish a crude compound. The crude product was purifiedwith flash column chromatography on silica gel (methanol indichloromethane, 8% v/v) to give Compound 362G.

Compound 362G (215 mg, 0.47 mmol) was dissolved in methanol (20 mL), and20% Pd(OH)₂ (45 mg) was added. The mixture was stirred under hydrogen atroom temperature overnight. After filtration, the filtrate wasevaporated to give the Compound 362H.

To a solution of Compound 362H (93 mg, 0.29 mmol) in dichloromethane (10mL) was added Compound 133D (70 mg, 0.29 mmol) and HATU (164 mg, 0.43mmol). The mixture was stirred under nitrogen at room temperatureovernight. The resulting mixture was quenched with saturated aqueoussodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50mL×3). The combined organic phases were washed with water (5 mL) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude compound. The crude product was purifiedwith prep-HPLC to furnish Compound 362. LC-MS (ESI) m/z: 551 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.23 (s, 3H), 1.28 (s, 3H), 1.88-2.02(m, 4H), 3.10-3.17 (m, 2H), 3.44-3.54 (m, 4H), 3.98 (s, 2H), 4.50 (s,1H), 4.77 (s, 1H), 6.01 (d, J=2.8 Hz, 1H), 6.72 (s, 1H), 6.81 (d, J=10.8Hz, 1H), 7.37 (t, J=8.4 Hz, 2H), 7.80-7.92 (m, 6H), 8.73 (d, J=9.2 Hz,1H), 9.31 (s, 1H).

Example 363

To a solution of Intermediate G (112 mg, 0.36 mmol) in dichloromethane(10 mL) was added Compound 359A (80 mg, 0.30 mmol) and HATU (171 mg,0.45 mmol). The mixture was stirred under nitrogen at room temperatureovernight. The resulting mixture was quenched with saturated aqueoussodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50mL×3). The combined organic phases were washed with water (5 mL) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude compound. The crude product was purifiedwith prep-HPLC to furnish Compound 363. LC-MS (ESI) m/z: 559 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.68-0.70 (m, 2H), 0.82-0.84 (m, 2H),1.87-1.91 (m, 2H), 2.02-2.04 (m, 2H), 3.11-3.20 (m, 2H), 3.47-3.55 (m,4H), 3.92-3.96 (m, 1H), 4.53-4.57 (m, 1H), 4.88 (s, 1H), 6.06 (d, J=3.2Hz, 1H), 7.27 (d, J=4.0 Hz, 1H), 7.34 (dd, J=8.8, 1.6 Hz, 1H), 7.41 (d,J=8.4 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.62 (d, J=4.0 Hz, 1H), 7.70-7.76(m, 4H), 8.78 (d, J=9.6 Hz, 1H), 9.48 (s, 1H).

Example 364

A mixture of Compound 3611 (100 mg, 0.306 mmol), Compound 242F (74 mg,0.306 mmol), and HATU (174 mg, 0.459 mmol) in dichloromethane (2 mL) wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (50 mL), washed with water (100 mL) and brine (50 mL),dried over anhydrous sodium sulfate, concentrated, and purified withprep-HPLC to give Compound 364. LC-MS (ESI) m/z: 549 [M+H]⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ (ppm) 1.17 (d, J=6.0 Hz, 3H), 1.25 (d, J=6.0 Hz,3H), 1.81-1.88 (m, 2H), 1.98-2.05 (m, 2H), 3.09-3.20 (m, 2H), 3.40-3.57(m, 4H), 3.71 (s, 3H), 4.44-4.56 (m, 2H), 4.78-4.80 (m, 1H), 6.10 (d,J=2.0 Hz, 1H), 6.80-6.86 (m, 2H), 7.54 (dd, J₁=1.6 Hz, J₂=8.4 Hz, 1H),8.13 (d, J=8.8 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.60 (d,J=9.6 Hz, 1H), 9.19 (brs, 1H).

Example 365

A mixture of 4-chloro-2-hydroxybenzaldehyde (1.56 g, 0.01 mol), diethyl2-bromomalonate (2.38 g, 0.01 mol), and K₂CO₃ (1.38 g, 0.01 mol) in2-butanone (80 mL) was refluxed overnight. After completion of thereaction, the resulting mixture was cooled down to room temperature,poured into water, acidified to pH 2 with dilute aqueous sulfuric acidsolution (2 N), and extracted with ether (40 mL×3). After removal of theorganic solvent, the residue was dissolved in alcoholic potash (preparedfrom 20 mL of alcohol and 2 g of solid potassium hydroxide) and refluxedfor 2 h. The solvent was concentrated and the residue was dissolved inwater (20 mL). The aqueous layer was acidified to pH 2 with diluteaqueous sulfuric acid solution (2 N) and solid was precipitated. Theformed solid were collected with filtration, washed with water (20 mL),and dried to afford Compound 365A.

A solution of Compound 365A (1.98 g, 10 mmol) and copper powder (0.4 g)were refluxed in quinoline (20 mL) for 2 h. After cooling down to roomtemperature, the mixture was diluted with ether (80 mL) and washed withdiluted aqueous HCl solution (2 N, 40 mL×3). The organic layer waswashed with water (30 mL) and brine (30 mL), dried over anhydrous sodiumsulfate, and carefully concentrated at 0° C. to give Compound 365B.

To a solution of Compound 365B (1.53 g, 10 mmol) in THF (30 mL) wasadded dropwise n-BuLi solution (2.5 Min hexane, 4 mL, 10 mmol) undernitrogen at −78° C. The mixture was stirred at −78° C. for 0.5 h and theabove solution was added to a solution of diethyl oxalate (3 g, 20 mmol)in THF (20 mL) under nitrogen at −78° C. The mixture was slowly warmedto room temperature and stirred at room temperature overnight. Themixture was quenched with saturated aqueous ammonium chloride solution(40 mL) and extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with water (100 mL) and brine (100 mL), dried overanhydrous sodium sulfate, and concentrated. The residue was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, from 10% to 50% v/v) to furnish Compound 365C.

To a solution of Compound 365C (2.4 g, 10 mmol) in THF/H₂O (40 mL/10 mL)was added LiOH H₂O (840 mg, 20 mmol). The mixture was stirred at roomtemperature for about 2 h until completion by thin layer chromatographyanalysis. The reaction mixture was acidified to pH 2 with dilutedaqueous HCl solution (1.0 N, 40 mL) and extracted with ethyl acetate (30mL×2). The combined organic layers were washed with water (100 mL) andbrine (100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to yield Compound 365D.

To a mixture of Compound 365D (112 mg, 0.5 mmol) and Intermediate G (155mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was diluted with ethyl acetate (50 mL), washed withwater (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified with prep-HPLC tofurnish Compound 365. LC-MS (ESI) m/z: 517 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.63-0.79 (m, 4H), 1.88-1.99 (m, 4H), 3.13-3.21 (m, 2H),3.38-3.56 (m, 4H), 3.88-3.89 (m, 1H), 4.43-4.45 (m, 1H), 4.78-4.79 (m,1H), 6.04 (s, 1H), 7.27-7.39 (m, 3H), 7.47-7.49 (m, 1H), 7.93 (d, J=8.4Hz, 1H), 8.01 (s, 1H), 8.20 (s, 1H), 8.62 (d, J=10.0 Hz, 1H), 9.07 (brs,1H).

Example 366

To a mixture of Compound 365D (114 mg, 0.5 mmol) and Intermediate C (143mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). Thereaction mixture was stirred at room temperature overnight. Theresulting solution was diluted with ethyl acetate (30 mL), washed withwater (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified with prep-HPLC tofurnish Compound 366. LC-MS (ESI) m/z: 503 [M+H]⁺; 1H-NMR (DMSO-d₆, 400MHz): δ (ppm) 1.84-2.01 (m, 4H), 3.11-3.13 (m, 2H), 3.31-3.54 (m, 4H),4.23-4.27 (m, 4H), 4.40-4.43 (m, 1H), 4.71 (s, 1H), 6.04 (br s, 1H),6.72 (s, 1H), 6.77-6.81 (m, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4Hz, 1H), 8.02 (s, 1H), 8.26 (s, 1H), 8.60 (d, J=9.6 Hz, 1H), 9.04 (br s,1H).

Example 367

A mixture of Compound 273C (66 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol),and Intermediate H (85 mg, 0.3 mmol) in DMF (5 mL) was stirred at 25° C.for 16 h. The mixture was diluted with ethyl acetate (30 mL), washedwith water (10 mL×2) and brine (10 mL), dried over anhydrous sodiumsulfate, and concentrated to yield a crude compound. The crude productwas purified with prep-HPLC to furnish Compound 367. LC-MS (ESI) m/z:484 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.97-2.00 (m, 4H),2.24-2.27 (m, 1H), 2.38-2.43 (m, 1H), 3.31-3.35 (m, 6H), 4.07-4.16 (m,4H), 4.28-4.33 (m, 5H), 4.72 (s, 1H), 6.00 (s, 1H), 6.52-6.54 (m, 2H),6.72-6.80 (m, 2H), 7.64-7.66 (m, 2H), 8.43 (d, J=10 Hz, 1H), 9.84 (s,1H).

Example 368

A mixture of Intermediate G (177 mg, 0.57 mmol), Compound 368A (117 mg,0.52 mmol), and HATU (350 mg, 0.92 mmol) in DMF (5 mL) was stirred atroom temperature overnight. The mixture was diluted with dichloromethane(100 mL), washed with water (50 mL×2) and brine (50 mL), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to give Compound 368. LC-MS (ESI) m/z: 528.2[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.72-0.86 (m, 4H), 2.03-2.23(m, 4H), 3.21-3.31 (m, 2H), 3.40-3.43 (m, 4H), 3.55-3.58 (m, 1H),3.68-3.74 (m, 2H), 3.79-3.89 (m, 6H), 4.70-4.73 (m, 1H), 4.98 (d, J=2.8Hz, 1H), 6.84 (d, J=9.2 Hz, 2H), 7.38 (s, 2H), 7.44-7.47 (m, 3H).

Example 369

A mixture of Intermediate H (100 mg, 0.42 mmol), Compound 368A (141 mg,0.50 mmol), and HATU (290 mg, 0.76 mmol) in DMF (5 mL) was stirred atroom temperature overnight. The mixture was diluted with dichloromethane(100 mL), washed with water (50 mL×2) and brine (50 mL), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to give Compound 369. LC-MS (ESI) m/z: 500.2[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 2.40-2.68 (m, 2H), 3.40-3.43(m, 4H), 3.51-3.75 (m, 3H), 3.82-3.85 (m, 4H), 4.06-4.20 (m, 1H),4.20-4.34 (m, 9H), 4.34-4.49 (m, 1H), 4.86 (d, J=3.2 Hz, 1H), 6.77-6.80(m, 2H), 6.93 (d, J=9.2 Hz, 2H), 7.64 (d, J=9.2 Hz, 2H).

Example 370

A mixture of Compound 175A (200 mg, 1.23 mmol), ethyl2-(4-bromophenyl)-2-oxoacetate (316 mg, 1.23 mmol), Pd(dppf)Cl₂ (49 mg,0.06 mmol), and K₂CO₃ (509 mg, 3.69 mmol) in 1,4-dioxane (10 mL) andwater (10 mL) was stirred under nitrogen at 100° C. for 3 h. Thereaction mixture was cooled down to room temperature and filteredthrough celite. The filtrate was diluted with water (100 mL) andextracted with ethyl acetate (100 mL×2). The aqueous layer was acidifiedto pH 3 with aqueous HCl solution (1 N) and extracted withdichloromethane (100 mL×3). The combined dichloromethane layers werewashed with water (50 mL), dried over anhydrous sodium sulfate, andconcentrated to give Compound 370A.

A mixture of Compound 370A (65 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol),and Intermediate G (74 mg, 0.24 mmol) in DMF (5 mL) was stirred at 25°C. overnight. The mixture was directly purified with prep-HPLC tofurnish Compound 370. LC-MS (ESI) m/z: 559 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.65-0.85 (m, 6H), 0.99-1.03 (m, 2H), 1.90-2.02 (m, 5H),3.12-3.19 (m, 2H), 3.41-3.55 (m, 4H), 3.91-3.96 (m, 1H), 4.55-4.59 (m,1H), 4.91 (s, 1H), 6.07 (s, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.35 (dd,J=8.4, 1.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.64(d, J=8.8 Hz, 2H), 7.71-7.74 (m, 4H), 8.80 (d, J=9.6 Hz, 1H), 9.67 (brs,1H).

Example 371

A mixture of Compound 370A (65 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol),and Intermediate C (71 mg, 0.24 mmol) in DMF (5 mL) was stirred at 25°C. overnight. The mixture was directly purified with prep-HPLC tofurnish Compound 371. LC-MS (ESI) m/z: 545 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.72-0.76 (m, 2H), 0.99-1.03 (m, 2H), 1.88-2.02 (m, 5H),3.11-3.14 (m, 2H), 3.26-3.55 (m, 4H), 4.23-4.29 (m, 4H), 4.49-4.54 (m,1H), 4.80 (s, 1H), 6.05 (d, J=4.0 Hz, 1H), 6.77 (s, 1H), 6.83 (dd,J=12.0, 1.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H),7.78 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 8.74 (d, J=9.6 Hz, 1H),9.51 (brs, 1H).

Example 372

To a solution of tetrahydro-4H-pyran-4-one (380 mg, 3.8 mmol) and1-bromo-4-iodobenzene (2.4 g, 8.5 mmol) in dry THF (50 mL) was addeddropwise n-BuLi (2.5 M solution in hexane, 1.52 mL, 3.8 mmol) undernitrogen at −78° C. over a period of 15 min. The resulting solution wasallowed to warm slowly to room temperature and stirred for 3.5 h. Theresulting mixture was quenched with saturated aqueous ammonium chloridesolution (10 mL) and extracted with ethyl acetate (50 mL×3). The organiclayer was washed with water (10 mL) and brine (10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to yield a crudeproduct. The crude product was purified with flash column chromatographyon silica gel (ethyl acetate, 100% v/v) to furnish Compound 372A.

To a solution of Compound 372A (620 mg, 2.42 mmol) in drydichloromethane (10 mL) was added triethylsilane (0.43 mL, 2.71 mmol).Trifluoroacetic acid (1.83 mL, 24.2 mmol) was added dropwise. After onehour at −78° C., the mixture was warmed to room temperature and stirredfor 3 h. The resulting mixture was quenched with aqueous NaOH solution(1 N, 5 mL) and extracted with dichloromethane (50 mL×3). The organiclayer was washed with water (10 mL) and brine (10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated to yield a crudeproduct. The crude product was purified with flash column chromatographyon silica gel (ethyl acetate in petroleum ether, 80% v/v) to affordCompound 372B.

To a solution of Compound 372B (295 mg, 1.23 mmol) in dry THF (20 mL)was added dropwise n-BuLi (2.5 M solution in hexane, 0.74 mL, 1.84 mmol)under nitrogen at −78° C. After stirring for 30 min, diethyl oxalate(449 mg, 3.07 mmol) was added in one portion. The mixture was stirred at−78° C. for about an hour. The resulting mixture was quenched withsaturated aqueous ammonium chloride solution (10 mL) and extracted withethyl acetate (50 mL×3). The organic layer was washed with water (5 mL)and brine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to yield a crude product. The crude product was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 10% v/v) to furnish Compound 372C.

To a solution of Compound 372C (155 mg, 0.59 mmol) in THF (10 mL) wasadded dropwise a solution of LiOH.H₂O (50 mg, 1.18 mmol) in water (3mL). The mixture was stirred at room temperature for 3 h. The reactionsolution was adjusted to pH 3 with aqueous HCl solution (1 N, 1.5 mL)and separated. The organic layer was dried directly over anhydroussodium sulfate, filtered, and concentrated to afford Compound 372D.

To a solution of Intermediate G (87 mg, 0.28 mmol) in dichloromethane(10 mL) was added Compound 372D (55 mg, 0.23 mmol) and HATU (134 mg,0.35 mmol) under nitrogen. The mixture was stirred at room temperatureovernight. The resulting mixture was diluted with saturated aqueoussodium bicarbonate solution (5 mL) and extracted with dichloromethane(50 mL×3). The combined organic phases were washed with water (5 mL) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude product. The crude product was purifiedwith prep-HPLC to furnish Compound 372. LC-MS (ESI) m/z: 527 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.68-0.84 (m, 4H), 1.62-1.69 (m, 4H),1.87-2.03 (m, 4H), 2.83-2.91 (m, 1H), 3.11-3.20 (m, 2H), 3.44-3.54 (m,6H), 3.95-3.97 (m, 3H), 4.53-4.58 (m, 1H), 4.87 (s, 1H), 6.05 (d, J=4.0Hz, 1H), 7.34-7.42 (m, 5H), 7.62 (d, J=8.4 Hz, 2H), 8.76 (d, J=9.6 Hz,1H), 9.51 (s, 1H).

Example 373

To a solution of Intermediate C (83 mg, 0.28 mmol) in dichloromethane(10 mL) was added Compound 372D (55 mg, 0.23 mmol) and HATU (134 mg,0.35 mmol) under nitrogen. The mixture was stirred at room temperatureovernight. The resulting mixture was diluted with saturated aqueoussodium bicarbonate solution (5 mL) and extracted with dichloromethane(50 mL×3). The combined organic phases were washed with water (5 mL) andbrine (5 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a crude product. The crude product was purifiedwith prep-HPLC to furnish Compound 373. LC-MS (ESI) m/z: 513 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.66-1.71 (m, 4H), 1.87-2.02 (m, 4H),2.85-2.91 (m, 1H), 3.10-3.16 (m, 2H), 3.48-3.54 (m, 6H), 3.95-3.98 (m,2H), 4.26-4.29 (m, 4H), 4.47-4.52 (m, 1H), 4.77 (s, 1H), 6.03 (d, J=2.4Hz, 1H), 6.75 (s, 1H), 6.81 (dd, J=11.2, 1.6 Hz, 1H), 7.40 (d, J=8.4 Hz,2H), 7.74 (d, J=8.4 Hz, 2H), 8.70 (d, J=9.6 Hz, 1H), 9.42 (s, 1H).

Example 374

A mixture of Intermediate X (77 mg, 0.34 mmol), Compound 368A (55 mg,0.24 mmol), and HATU (175 mg, 0.46 mmol) in DMF (5 mL) was stirred atroom temperature overnight. The mixture was diluted with dichloromethane(100 mL), washed with water (50 mL×2) and brine (50 mL), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to give Compound 374. LC-MS (ESI) m/z: 494.2[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.68-0.69 (m, 2H), 0.77-0.81(m, 2H), 2.05-2.22 (m, 5H), 3.20-3.30 (m, 2H), 3.40-3.42 (m, 4H),3.53-3.60 (m, 1H), 3.66-3.72 (m, 2H), 3.76-3.85 (m, 7H), 4.66-4.69 (m,1H), 4.97 (d, J=2.8 Hz, 1H), 6.88 (d, J=9.2 Hz, 2H), 7.04 (d, J=8.4 Hz,2H), 7.37 (d, J=8.4 Hz, 2H), 7.60 (d, J=9.2 Hz, 2H).

Example 375

To a solution of aniline (9.3 g, 100 mmol) in DMF (350 mL) was addedcesium carbonate (100 g, 306 mmol) and 1, 3-dibromopropane (27 g, 135mmol). The mixture was stirred for 24 h while keeping inner temperaturebetween 60° C. and 65° C. After the reaction mixture was cooled toambient temperature, the dark solution was diluted with water (400 mL)and extracted with ethyl acetate (300 mL×3). The combined organic phaseswere washed with brine (150 mL×4), dried over anhydrous sodium sulfate,filtered, and concentrated to afford the crude product as a brown oil.The crude product was purified with flash column chromatography onsilica gel (petroleum ether) to furnish Compound 375A.

To a solution of compound 375A (900 mg, 6.8 mmol) and aluminumtrichloride (5.0 g, 37.9 mmol) in dichloromethane (30 mL) was addeddropwise ethyl 2-chloro-2-oxoacetate (1.06 g, 8.0 mmol) at 0° C. Themixture was stirred for 4 hours while keeping the temperature at 0° C.The mixture was poured into ice water and extracted with ethyl acetate(50 mL×3). The resulting product was concentrated under reducedpressure, and the resultant residue was purified with silica gel columnchromatography (ethyl acetate in petroleum ether, 30% v/v) to giveCompound 375B.

To a solution of Compound 375B (333 mg, 1.00 mmol) in MeOH (10 mL) wasadded LiOH.H₂O (90 mg, 2.14 mmol) and water (2 mL). The reaction mixturewas stirred at 15° C. for 4 h. The reaction mixture was neutralized withHCl (1 N). The resulting mixture was evaporated. The residue wasdissolved in water (5 mL). The mixture was extracted with ethyl acetate(10 mL×2), dried over anhydrous sodium sulfate, filtered, and evaporatedto give Compound 375C.

A mixture of Intermediate G (203 mg, 0.65 mmol), Compound 375C (110 mg,0.53 mmol), and HATU (350 mg, 0.92 mmol) in DMF (5 mL) was stirred atroom temperature overnight. The mixture was diluted with dichloromethane(150 mL), washed with water (100 mL×2) and brine (100 mL), dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified with prep-HPLC to give Compound 375. LC-MS (ESI) m/z: 498.2[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): δ (ppm) 0.69-0.87 (m, 4H), 1.90-2.26(m, 4H), 3.01-3.27 (m, 2H), 3.43-3.68 (m, 4H), 3.70-3.95 (m, 2H),4.19-4.42 (m, 2H), 4.77 (s, 1H), 4.98-5.17 (m, 2H), 5.53-5.92 (m, 1H),6.96-7.31 (m, 5H), 7.36-7.57 (m, 3H).

Example 376

A mixture of 1-(4-fluorophenyl)ethan-1-one (5.00 g, 36.20 mmol) and SeO₂(6.06 g, 54.30 mmol) in pyridine (20 mL) was stirred at 70° C. for 16 h.After filtration to remove the resultant solid, the filtrate wasevaporated to give a residue. The crude product was dissolved in aqueoussodium hydroxide solution (1 M, 20 mL) and water (50 mL) and extractedwith diethyl ether (160 mL) to remove by-product. The aqueous solutionwas adjusted to pH 1 with concentrated hydrochloride acid (4 mL) andextracted with dichloromethane (100 mL×3). The organic layer was washedwith brine (50 mL), dried over anhydrous sodium sulfate, and evaporatedto afford Compound 376A.

A mixture of Compound 376A (54 mg, 0.32 mmol), Intermediate G (100 mg,0.32 mmol), and HATU (183 mg, 0.48 mmol) in dichloromethane (3 mL) wasstirred at 20° C. for 16 h. The mixture was diluted with ethyl acetate(100 mL), washed with water (100 mL) and brine (100 mL), dried overanhydrous sodium sulfate, and evaporated to give a residue. The crudeproduct was purified with prep-HPLC to afford Compound 376. LC-MS (ESI)m/z: 461 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 0.66-0.83 (m, 4H),1.86-2.02 (m, 4H), 3.12-3.18 (m, 2H), 3.46-3.53 (m, 4H), 3.89-3.95 (m,1H), 4.48-4.55 (m, 1H), 4.85 (s, 1H), 6.08 (s, 1H), 7.30-7.42 (m, 5H),7.89 (t, J=8.8 Hz, 2H), 8.74 (d, J=9.6 Hz, 1H), 9.57 (s, 1H).

Example 377

To a solution of benzo[b]thiophene (1 g, 7.5 mmol) in THF (25 mL) wasadded dropwise n-BuLi (3.6 mL, 8.9 mmol) under nitrogen at −78° C. Theresulting mixture was stirred at −78° C. for 15 min. To the resultingmixture was added diethyl oxalate (3.3 g, 8.9 mmol) quickly. The mixturewas stirred for 1 h at −78° C., quenched with sat. ammonium chloridesolution, treated with water (50 mL), extracted with ethyl acetate (50mL×2), washed with brine (50 mL), dried over anhydrous sodium sulfate,concentrated, and purified with flash column chromatography on silicagel (petroleum ether) to furnish Compound 377A.

To a solution of Compound 377A (1.5 g, 6.4 mmol) in THF (50 mL) wasadded dropwise LiOH.H₂O (538 mg, 12.8 mmol) in water (4 mL) at −20° C.The resulting mixture was stirred at −20° C. for 1 h. The mixture wasadjusted to pH 1 with diluted HCl. The resulting mixture was extractedwith ethyl acetate (50 mL×2). The organic layer was concentrated,treated with petroleum ether (50 mL), and stirred for 30 min. The yellowsolid was formed and filtered to furnish Compound 377B.

A mixture of Compound 377B (100 mg, 0.48 mmol), Intermediate G (150 mg,0.48 mmol), and HATU (277 mg, 0.73 mmol) in DMF (5 mL) was stirred atroom temperature for 12 h. The mixture was treated with water (10 mL),extracted with dichloromethane (20 mL×2), washed with water (20 mL×3)and brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with prep-HPLC to furnish Compound 377. LC-MS (ESI) m/z:499 [M+H]⁺; ¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 0.60-0.81 (m, 4H),2.23 (s, 2H), 2.93 (s, 3H), 3.50 (s, 2H), 3.81-3.85 (m, 2H), 4.00-4.06(m, 3H), 4.86 (t, J=7.2 Hz, 1H), 5.15 (d, J=2.8 Hz, 1H), 7.33-7.41 (m,2H), 7.47-7.53 (m, 2H), 7.61 (t, J=7.2 Hz, 1H), 8.04-8.09 (m, 2H),8.14-8.19 (m, 1H), 8.64 (s, 1H), 9.52 (s, 1H).

Example 378

To a solution of compound 175A (2.57 g, 10.0 mmol), CuI (190 mg, 1.0mmol), and Pd(PPh₃)₂Cl₂ (210 mg, 0.3 mmol) in triethylamine (80 mL) wasadded dropwise ethynyltrimethylsilane (1.17 g, 12.0 mmol) under nitrogenatmosphere at room temperature. The reaction mixture was stirred at 90°C. for 30 minutes. Solids were collected with filtration and washed withacetate ethyl (80 mL×2). The filtrate was concentrated under reducedpressure to give a residue, which was purified with flash columnchromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v)to yield compound 378A.

To a solution of Compound 378A (500 mg, 1.8 mmol) in THF (5 mL) wasadded LiOH.H₂O (113 mg, 2.7 mmol) in water (2.0 mL). The resultingmixture was stirred at room temperature for 2 h, evaporated, treatedwith water (5 mL), and adjusted to pH 2 with diluted HCl. The mixturewas extracted with ethyl acetate (10 mL×3), washed with brine (10 mL),dried over anhydrous sodium sulfate, and concentrated to afford theCompound 378B.

To a solution of Compound 378B (34 mg, 0.2 mmol) in DMF (3 mL) was addedIntermediate S (59 mg, 0.2 mmol) and HATU (114 mg, 0.3 mmol). Thereaction mixture was stirred at room temperature for 4 h. The mixturewas purified with prep-HPLC to give Compound 378. LC-MS (ESI) m/z: 451[M+H]⁺; ¹H-NMR (acetone-d₆, 400 MHz): δ (ppm) 0.68-0.70 (m, 2H),0.79-0.81 (m, 2H), 2.04-2.09 (m, 4H), 3.60-3.63 (m, 3H), 3.88-3.93 (m,5H), 4.00 (s, 1H), 4.81-4.83 (m, 1H), 5.15 (d, J=2.8 Hz, 1H), 7.23-7.25(m, 2H), 7.33-7.35 (m, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz,2H), 8.15-8.18 (m, 1H), 9.31 (brs, 1H).

Example 379

A mixture of Compound 376A (54 mg, 0.32 mmol), Intermediate C (95 mg,0.32 mmol), and HATU (183 mg, 0.48 mmol) in dichloromethane (3 mL) wasstirred at 20° C. for 16 h. The mixture was diluted with ethyl acetate(100 mL), washed with water (100 mL) and brine (100 mL), dried overanhydrous sodium sulfate, and evaporated to give a residue. The crudeproduct was purified with prep-HPLC to afford Compound 379. LC-MS (ESI)m/z: 447 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400 MHz): δ (ppm) 1.83-2.04 (m, 4H),3.07-3.19 (m, 2H), 3.41-3.47 (m, 4H), 4.27 (s, 4H), 4.42-4.50 (m, 1H),4.75 (s, 1H), 6.04 (s, 1H), 6.74 (s, 1H), 6.80 (d, J=10.4 Hz, 1H), 7.36(t, J=8.8 Hz, 2H), 7.93-7-98 (m, 2H), 8.70 (d, J=9.6 Hz, 1H), 9.40 (s,1H).

Example 380

A mixture of ethyl piperidine-4-carboxylate (10 g, 64 mmol),1-fluoro-4-iodobenzene (14 g, 64 mmol), K₂CO₃ (17.6 g, 127 mmol), andL-proline (1.46 g, 12.7 mmol) in DMSO (50 mL) was stirred under nitrogenat 85° C. for 12 h. The resulting mixture was added NH₃.H₂O (50 mL),extracted with ethyl acetate (100 mL×2), washed with water (100 mL×3)and brine (100 mL), dried over anhydrous sodium sulfate, concentrated,and purified with flash column chromatography on silica gel (ethylacetate in petroleum ether, 10% v/v) to furnish Compound 380A.

To a solution of AlLiH₄ (1.2 g, 31 mmol) in THF (100 mL) was addedCompound 380A (7.9 g, 31 mmol) in THF (50 mL) dropwise under nitrogen at−78° C. The resulting mixture was stirred at −78° C. for 1.5 h, quenchedwith Na₂SO₄.10H₂O. The mixture was treated with silica gel and filtered.The filtrate was concentrated and the resulting residue was purifiedwith flash column chromatography on silica gel (ethyl acetate inpetroleum ether, 20% v/v) to afford Compound 380B.

To a cooled −78° C. solution of oxalyl chloride (9.1 g, 72 mmol) indichloromethane (150 mL) was added dropwise DMSO (7.5 g, 96 mmol),maintaining the internal temperature below −40° C. After 30 min,Compound 380B (5 g, 24 mmol) in dichloromethane (10 mL) was addeddropwise to the reaction mixture. The reaction mixture was stirred at−78° C. for 45 min, triethylamine (12 g, 120 mmol) was added dropwise,and the mixture was warmed to room temperature stirred for 2 h. Themixture was treated with water (100 mL), extracted with dichloromethane(50 mL×2), washed with water (50 mL×2), dried over anhydrous sodiumsulfate, concentrated, and purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, 20% v/v) to furnishCompound 380C.

Compound 380C (3.3 g, 16 mol) was added to a solution of Na₂S₂O₅ (3 g,16 mol) in water (100 mL). The mixture was stirred for 2 h at roomtemperature. After the addition of NaCN (1.6 g, 32 mmol) the resultingmixture was stirred for 15 h, diluted with ethyl acetate (50 mL),extracted with ethyl acetate (100 mL×2), washed with sat. sodiumbicarbonate (100 mL×2) and brine (100 mL), dried over anhydrous sodiumsulfate, and concentrated to afford the crude Compound 380D.

To a solution of Compound 380D (3.7 g, 15.8 mmol) in ethanol (80 mL)cooled to 0° C. was bubbled a gentle stream of HCl gas (dried over con.H₂SO₄) for 5 h. The mixture was treated with water slowly at 0° C.,stirred at room temperature for 2 h, adjusted to pH 8 with NaOH (1 M),extracted with dichloromethane (50 mL×2), washed with brine (100 mL),dried over anhydrous sodium sulfate, and concentrated to give Compound380E.

To a cooled −78° C. solution of oxalyl chloride (3.66 g, 28.8 mmol) indichloromethane (50 mL) was added dropwise DMSO (3 g, 38.4 mmol),maintaining the internal temperature below −40° C. After 30 min,Compound 380E (2.7 g, 9.6 mmol) in dichloromethane (10 mL) was addeddropwise to the reaction mixture. The reaction mixture was stirred at−78° C. for 45 min, triethylamine (4.85 g, 48 mmol) was added dropwise,and the mixture was warmed to room temperature stirred for 2 h. Themixture was treated with water (100 mL), extracted with dichloromethane(50 mL×2), washed with water (50 mL×2), dried over anhydrous sodiumsulfate, concentrated, and purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, 20% v/v) to furnishCompound 380F.

To a solution of Compound 380F (878 mg, 3.14 mmol) in THF (20 mL) wasadded LiOH.H₂O (264 mg, 6.29 mmol) in water (2 mL) at −30° C. Theresulting mixture was stirred at −30° C. for 2 h, evaporated, treatedwith water, adjusted to pH 2 with diluted HCl, and lyophilized. Thesolid was purified with reverse phase chromatography using eluent(acetonitrile in water, from 1% to 100% v/v) to furnish Compound 380G.

A mixture of Compound 380G (300 mg, 1.19 mmol), Intermediate G (370 mg,1.19 mmol), and HATU (681 mg, 0.73 mmol) in DMF (15 mL) was stirred atroom temperature for 12 h. The mixture was treated with water (10 mL),extracted with dichloromethane (20 mL×2), washed with water (20 mL×3)and brine (50 mL), dried over anhydrous sodium sulfate, concentrated,and purified with reverse phase chromatography eluting with(acetonitrile in water, from 1% to 100% v/v) to furnish Compound 380.LC-MS (ESI) m/z: 544 [M+H]⁺; ¹H-NMR (acetone-d₆, 400 MHz): δ (ppm)0.69-0.84 (m, 4H), 1.68 (s, 1H), 1.92-2.13 (m, 9H), 3.15-3.37 (m, 4H),3.62-3.69 (m, 3H), 3.82-3.89 (m, 4H), 4.65-4.68 (m, 1H), 5.09 (s, 1H),7.14-7.19 (m, 1H), 7.34-7.40 (m, 5H), 7.79-7.81 (m, 1H), 8.21 (s, 1H),11.31 (s, 1H).

Example 381

A mixture of Intermediate Y (70 mg, 0.25 mmol), HATU (143 mg, 0.37mmol), and Compound 242F (60 mg, 0.25 mmol) in DMF (5 mL) was stirred at25° C. overnight. The mixture was directly purified with prep-HPLC tofurnish Compound 381. LC-MS (ESI) m/z: 503 [M+H]⁺; ¹H-NMR (DMSO-d₆, 400MHz): δ (ppm) 0.61-0.79 (m, 4H), 2.24-2.42 (m, 2H), 3.33-3.49 (m, 2H),3.82-3.91 (m, 1H), 4.02-4.33 (m, 5H), 4.77 (d, J=4.0 Hz, 1H), 6.03 (brs,1H), 7.13-7.20 (m, 2H), 7.36 (t, J=8.4 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz,1H), 8.12 (d, J=8.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.56(d, J=10.0 Hz, 1H), 9.44 (brs, 1H).

Example 382

To a solution of AlLiH₄ (76 mg, 2 mmol) in THF (15 mL) was addedIntermediate S7 (430 mg, 1 mmol) in THF (5 mL) dropwise under nitrogenatmosphere. The resulting mixture was stirred at 60° C. for 3 h andquenched with aqueous Na₂SO₄ solution. The filtrate was concentrated toafford a crude product, which was purified by prep-HPLC to give Compound382A (240 mg, yield 78%). LC-MS (ESI) m/z: 309 [M+H]⁺; ¹H-NMR (CDCl₃,400 MHz): δ (ppm) 0.75-0.85 (m, 4H), 1.76-1.79 (m, 4H), 2.34 (s, 3H),2.43-2.59 (m, 6H), 2.87-2.91 (m, 1H), 3.77-3.82 (m, 1H), 4.63-4.69 (m,1H), 7.02-7.12 (m, 2H), 7.22-7.26 (m, 1H).

A mixture of Compound 382A (92 mg, 0.33 mmol), Compound 133D (73 mg,0.30 mmol), and HATU (137 mg, 0.36 mmol) in DMF (4 mL) was stirred at25° C. for 4 h. Then it was purified by prep-HPLC to give Compound 382(70 mg, yield 36%) as a white solid. LC-MS (ESI) m/z: 535 [M+H]⁺; ¹H-NMR((CD₃)₂CO, 400 MHz): δ (ppm) 0.61-0.90 (m, 4H), 2.06-2.25 (m, 4H),3.08-3.27 (m, 3H), 3.45 (s, 2H), 3.71-4.46 (m, 5H), 5.08-5.38 (m, 1H),5.57-5.72 (m, 1H), 6.88-7.85 (m, 11H), 9.20-9.95 (m, 1H).

Example 383

A mixture of Compound 382A (140 mg, 0.45 mmol), Compound 242F (98 mg,0.40 mmol), and HATU (182 mg, 0.48 mmol) in DMF (3 mL) was stirred at25° C. for 15 h. It was purified by prep-HPLC to give Compound 383 (88mg, yield 34%) as a white solid. LC-MS (ESI) m/z: 531 [M+H]⁺; ¹H-NMR(DMSO-d, 400 MHz): δ (ppm) 0.30-0.84 (m, 4H), 1.88-2.04 (m, 4H),2.99-3.29 (m, 6H), 3.55-3.69 (m, 2H), 3.81-4.08 (m, 2H), 4.31-4.78 (m,1H), 4.95-5.15 (m, 1H), 6.04-6.19 (m, 1H), 6.90-7.71 (s, 5H), 7.86-8.12(m, 1H), 8.26-8.32 (m, 1H), 9.38-9.53 (m, 1H).

Biological Examples

The following describes ways in which the compounds described hereinwere tested to measure in vitro activity in enzymatic and cell-basedassays. A person of ordinary skill in the art would know that variationsin the assay conditions could be used to determine the activity of thecompounds.

Assay 1: GCS Enzymatic Assay

This assay was modified based on the study by Larsen et al. (J. LipidRes. 2011, 53, 282). Madin-Darby canine kidney (MDCK) cell lysate wasprepared using M-PER Mammalian Protein Extraction Reagent (ThermalScientific) in the presence of a protease inhibitor cocktail (Roche).Protein concentration was determined using BCA assay kit (Pierce). Sixtymicrograms of MDCK cell lysate was incubated with various concentrationsof a compound described herein from 0.001 μM-10 μM, respectively, in 100mM Tris buffer (pH 7.5) containing 10 mM MgCl₂, 1 mM dithiothreitol, 1mM EGTA, 2 mM NAD, 100 μM UDP-glucose, 10 μM C6-NBD-Ceramide (MatreyaLLC, Pleasant Gap, Pa.), 35 μM dioleoylphosphatidylcholine and 5 μMsulfatide (Sigma) in a final reaction volume of 100 μL at 37° C. for 1hour. 0.1% DMSO was used as mock treatment or control. The reaction wasterminated by adding 100 μL acetonitrile solution and subjected to LC/MSanalysis.

The quantitative analysis of NBD-Ceramide and glucosylceramide wasperformed on a Shimadzu ultra-fast liquid chromatography (Shimadzu,Japan) coupled with API 4000 triple quadrupole mass spectrometer(Applied Biosystems, Concord, Ontario, Canada). Sample separation wasconducted on a Waters Xbridge™ BEH130 C18, 100 mm×4.6 mm i.d, 3.5 μm(Milford, Mass., USA). The mobile phase consisted of water andacetonitrile supplemented with 0.1% formic acid (v/v). The flow rate was1.0 mL/min. The initial mobile phase was 20% acetonitrile and was rampedin a linear fashion to 50% acetonitrile in 0.4 min. From 0.4 to 1.5 min,the gradient was ramped to 98% acetonitrile, and then was held at 100%until 8.0 min. Acetonitrile was reset to 20% in 1.5 min, and maintaineduntil 10.0 min. The total run time was 10.0 min. The MS/MS detection wasperformed in ESI positive mode. The mass transition of NBD-Ceramide wasm/z 576.36-558.40 under the collision energy of 15 V, and the masstransition of glucosylceramide was m/z 738.35-558.40 under 21V collisionenergy. The cell lysate was diluted with equal volume of acetonitrile.Aliquots of 50 μL diluted samples were added to 1.5 mL tubes, and 100 μLof acetonitrile containing internal standard (100 ng/mL tolbutamide)were added for protein precipitation. The mixture were vortexed and thencentrifuged at 13000 rpm for 10 min. 70 μL of supernatant were mixedwith 140 μL of H₂O and the final solution were injected for LC/MS/MSanalysis and IC₅₀'s and/or percent inhibitions calculated.

Assay 2: K₅₆₂ Cell-Based Assay

This assay was modified based on the study by Gupta et al. (J. LipidRes. 2010, 51, 866). K562 cells were seeded into 12-well plates at 3×10⁵cells/well/mL in RPMI-1640 medium with 5% FBS and incubated at 37° C.for 24 h. One μL of a compound described herein at desired concentration(10 mM, 1 mM, 0.1 mM, 0.01 mM, 0.001 mM and 0.0001 mM in DMSO) or DMSOwas added into corresponding well and mixed. Cells were incubated at 37°C. for 4 h. Then 100 μL of RPMI-1640 medium containing 110 μM ofNBD-Ceramide, 11% BSA, 5% FBS, and corresponding concentration of acompound described herein was added into each well and mixed. Cells wereincubated for additional 0.5 h at 37° C., followed by washing the cellswith ice-cold PBS (pH 7.4) twice with centrifugation and resuspendedwith 50 μL cold PBS+1% Triton X-100. The cell lysate was sonicated for15 min before adding equal volume of methanol for LCMS analysis. A smallaliquot of cell lysate was used to determine protein concentration byBCA assay kit.

The HPLC equipment and methods used in Assay 1 were used in this assayas well and IC₅₀'s were calculated.

Assay 3: NCI/ADR-Res Cell-Based Assay

NCI/ADR-RES cells were seeded into 12-well plates (4×10⁵ cells/well) inRPMI-1640 medium with 10% FBS and incubated at 37° C. for 24 h. Beforetreatment with a compound described herein, cell culture media wereremoved and replaced with 1 mL per well RPMI-1640 medium containing 5%FBS and a compound as described herein at desired concentrations (10 μM,1 μM, 0.1 μM, 0.01 μM, 0.001 μM, and 0.0001 μM), respectively, or 0.1%DMSO only. Cells were cultured for 4 hours at 37° C. followed byreplacing the media with RPMI-1640 containing 1% BSA and 10 μM ofC6-NBD-Ceramide in the present of a compound described herein, andincubated for additional 0.5 hour at 37° C. Cells were then washed twicewith ice-cold PBS (pH 7.4), scraped with 50 μL cold PBS+1% Triton X-100.The cell lysate was sonicated for 15 min before adding equal volume ofmethanol for LCMS analysis. A small aliquot of cell lysate was used todetermine protein concentration by BCA assay kit.

The HPLC equipment and methods used in Assay 1 were used in this assayas well and IC₅₀'s and % inhibition were calculated.

Using the above assays, the following compounds were tested. In thetables below, “nt” means that the compound was not tested in the assay.Either IC₅₀ or % inhibition data are included in the tables. The %inhibition data is identified by an asterix (“*”). For IC₅₀ data, “A”means the compound had an IC₅₀ of greater than zero but less than orequal to about 50 nM and “B” means the compound had an IC₅₀ is greaterthan about 50 but less than or equal to about 5000 nM. For % inhibitiondata, “A*” means the compound had a % inhibition of a percent inhibitionof greater than or equal to about 50% and “B*” means the compound had a% inhibition of greater than or equal to about 3% but less than about50%. Table 1. The data provided is the IC₅₀ (nM) generated from Assay 1,except as otherwise noted by *, which is % inhibition, also generatedfrom Assay 1.

TABLE 1 The data provided is the IC₅₀ (nM) generated from Assay 1,except as otherwise noted by *, which is % inhibition, also generatedfrom Assay 1. Cmpd No. Name Data  12-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide  22-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((1R,2R)-1-(2,3- Bdihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide  32-(5-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide  42-(5-chlorobenzo[b]thiophen-2-yl)-2,2-difluoro-N-((2R)-1-(3-fluoro- B*4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)acetamide  5A2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((2R)-1-(3-fluoro-4- Bmethoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)acetamide  52-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1S,2R)-1-(3-fluoro- A4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)acetamide  5B2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1R,2R)-1-(3-fluoro- B*4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)acetamide  62-(5-chlorobenzo[d]thiazol-2-yl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide  72-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide  82-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1R,2R)-1-(2-fluoro- B*5-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)acetamide  8J2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1S,2R)-1-(2-fluoro- B*5-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)acetamide 102-(5-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 112-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 12B2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1S,2R)-1-(7-fluoro- B2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 132-(7,8-dihydro-6H-cyclopenta[g]quinoxalin-7-yl)-N-((1R,2R)-1-(2,3- Bdihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 142-(5-chloro-1-methyl-1H-indol-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 152-(5,7-dichlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 16N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(3-(pyridin-2-yl)phenyl)butanamide 17N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- B(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-3-(naphthalen-2-yl)propanamide 18 2-(5,6-dichlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 192-(4,5-dichlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 20N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-3-(3-(pyridin-2-yl)phenyl)propanamide 21N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-iluoro-2,3-dihydro-1H-inden-2-yl)acetamide 22N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 22KN-((1S,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 232-(benzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2- difluoroacetamide24 N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-fluorobenzofuran-2-yl)acetamide 25 (E)-4-(4-chlorophenyl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluorobut-3-enamide 26N-((1R,2R)-3-(3-amino-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 28N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-fluorobenzo[b]thiophen-2-yl)acetamide 30N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(trifluoromethyl)benzofuran-2-yl)acetamide 312-(5-bromobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 32CN-((1S,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6- B*yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 32DN-((1R,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6- Ayl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 33A2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-(7-fluoro- B*2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 332-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-(7-fluoro- B*2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 34G2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-3- B*(pyrrolidin-1-yl)-1-(quinolin-6-yl)propan-2-yl)acetamide 342-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-3- A*(pyrrolidin-1-yl)-1-(quinolin-6-yl)propan-2-yl)acetamide 36C2-(5-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3,3-dimethylpyrrolidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide 37G2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-3- B*(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2- yl)acetamide37 2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-3- B*(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2- yl)acetamide38 2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-3-((S)-3-fluoropyrrolidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide 392-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-((R)-2-methylpyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 402-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-((S)-2-methylpyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 412-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-3-(3,3-difluoropyrrolidin-1- B*yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide 44HN-((1S,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 44N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 46 2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Bdihydrobenzo[b][1,4]dioxin-6-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide 47N-((1R,2R)-1-(3-chloro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 482-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(2-azaspiro[3.3]heptan-2-yl)propan-2-yl)-2,2-difluoroacetamide 492-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1- B(1-methyl-1H-indazol-5-yl)-3-(pyrrolidin-1-yl)propan-2- yl)acetamide 50N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)acetamide 51N-((1R,2R)-3-(2-azabicyclo[2.2.1]heptan-2-yl)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 52N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 53 N-((1R,2R)-3-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 542-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1- B*(1-methyl-1H-indazol-6-yl)-3-(pyrrolidin-1-yl)propan-2- yl)acetamide 54G2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-1- B*(1-methyl-1H-indazol-6-yl)-3-(pyrrolidin-1-yl)propan-2- yl)acetamide 562-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1- A(6-methoxypyridin-3-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 57BN-[2-(2H,3H-benzo[e]1,4-dioxan-6-yl)(1R)-2-hydroxy-1- A(pyrrolidinylmethyl)ethyl]-2-(5-chlorobenzo[d]furan-2-yl)-2,2-difluoroacetamide 57 2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-deutero-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 57C2-(5-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-deutero-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 592-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(3-(difluoromethyl)-4- Bmethoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 59I2-(5-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(3-(difluoromethyl)-4- B*methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 60 2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-dideutero-acetamide 61N-((1R,2R)-1-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- B*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 622-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3,3-dimethylazetidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide 632-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 642-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-(8-fluoro- A2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 65N-((1R,2R)-1-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 662-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(3-methylazetidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 672-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(3-chloro-4- Acyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 68G2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(5-chlorobenzofuran-2- B*yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 682-(5-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(5-chlorobenzofuran-2- B*yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 69N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(trifluoromethyl)benzofuran-2-yl)acetamide 69AN-((1S,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(trifluoromethyl)benzofuran-2-yl)acetamide 702-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 712-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 72(E)-2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide 73N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)acetamide 742-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide

TABLE 2 The data provided is the IC₅₀ (nM) generated from Assay 1,except as otherwise noted by *, which is % inhibition, also generatedfrom Assay 1. Cmpd No. Name Data  77N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4,5,6,7-tetrahydro-2H-isoindol-1-yl)acetamide  78N-((1R,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6- Ayl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2- oxoacetamide 79 N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2-oxoacetamide  802-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-1- B(6-isopropoxypyridin-3-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide  82N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(6-fluoronaphthalen-2-yl)butanamide  83 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide  84N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(6-fluoronaphthalen-2-yl)butanamide  852-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-3- A(pyrrolidin-1-yl)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-2-yl)acetamide  86 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2,2-difluoro-4-(6-fluoronaphthalen-2-yl)butanamide  872,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)butanamide  882,2-difluoro-4-(6-fluoronaphthalen-2-yl)-N-((1R,2R)-1-hydroxy-3- A*(pyrrolidin-1-yl)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-2-yl)butanamide  89 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2-oxoacetamide  90N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-oxobutanamide  912-(5-chloro-2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1R,2R)-1- B*hydroxy-3-(pyrrolidin-1-yl)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-2-yl)acetamide  92N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chloro-2,3-dihydro-1H-inden-2-yl)-2,2-difluoroacetamide  932-(5-chloro-2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1R,2R)-1- A(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide  94N-((1R,2R)-1-(3-chloro-4-isopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide  952-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide  96N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(3- A*methylazetidin-1-yl)propan-2-yl)-2,2-difluoro-4-(6-fluoronaphthalen-2-yl)butanamide  972,2-difluoro-4-(6-fluoronaphthalen-2-yl)-N-((1R,2R)-1-hydroxy-1- A*(6-isopropoxypyridin-3-yl)-3-(pyrrolidin-1-yl)propan-2- yl)butanamide 98 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2-(hydroxyimino)acetamide  992-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(6-cyclopropoxypyridin- A3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2- difluoroacetamide100 2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(3-methylazetidin-1-yl)propan-2-yl)-2-oxoacetamide 101N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin- A1-yl)propan-2-yl)-2,2-difluoro-4-(6-fluoronaphthalen-2- yl)butanamide102 (E)-2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(3-methylazetidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide 1032-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-1- B*(2-isopropoxypyridin-4-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 104(E)-2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide 105N-((1R,2R)-1-(3-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 106(E)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy- A3-(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide 1072,2-difluoro-N-((1R,2R)-1-hydroxy-1-(6-isopropoxypyridin-3-yl)-3- A(pyrrolidin-1-yl)propan-2-yl)-4-(naphthalen-2-yl)butanamide 1082,2-difluoro-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(6-(2,2,2- Btrifluoroethoxy)pyridin-3-yl)propan-2-yl)-4-(naphthalen-2- yl)butanamide109 2,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-A 6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(naphthalen-2-yl)butanamide 110N-((1R,2R)-1-(3-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 111N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-oxobutanamide 112(E)-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide 113N-((1S,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- B*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 1142,2-difluoro-4-(6-fluoronaphthalen-2-yl)-N-((1R,2R)-1-hydroxy-1- A*(2-isopropoxypyridin-4-yl)-3-(pyrrolidin-1-yl)propan-2- yl)butanamide115 (E)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide 1162-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(3-chloro-4- A((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 117N-((1S,2R)-1-(2,2-dimethylchroman-6-yl)-1-hydroxy-3-(pyrrolidin- B*1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 118(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Bdihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide 1192-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,2-dimethylchroman-6- A*yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 120N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin- A*1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 121N-((1R,2R)-1-(3-chloro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-1- B*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 122N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- A*hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2-oxoacetamide 123N-((1R,2R)-1-(3-chloro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-1- A*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 124N-((1S,2R)-1-(3-chloro-4-morpholinophenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 125N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 1262-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3- Afluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 127N-((1R,2R)-1-(3-chloro-4-morpholinophenyl)-1-hydroxy-3- B(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 128N-((1R,2R)-1-(4-(2-(azetidin-1-yl)ethoxy)-3-chlorophenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 129N-((1R,2R)-1-(3-chloro-4-(oxetan-3-yloxy)phenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 130N-((1R,2R)-1-(3-chloro-4-(oxetan-3-yloxy)phenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 131N-((1R,2R)-1-(4-(2-(azetidin-1-yl)ethoxy)-3-chlorophenyl)-1- A*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 132 2-(6-chloronaphthalen-2-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 133N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 134N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- A*hydroxypropan-2-yl)-2,2-difluoro-4-(6-fluoronaphthalen-2- yl)butanamide135 2-(6-chloronaphthalen-2-yl)-2,2-difluoro-N-((1R,2R)-1-(8-fluoro- A2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 136(E)-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2-(hydroxyimino)acetamide 137(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4- B*cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide 138(E)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-(hydroxyimino)acetamide 139N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2-(6-chloronaphthalen-2-yl)-2,2-difluoroacetamide 1402,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 141(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(hydroxyimino)-4-(naphthalen-2-yl)butanamide 142(E)-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)-4-(naphthalen-2-yl)butanamide 143N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(naphthalen-2-yl)-2-oxobutanamide 144N-((1R,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6- Ayl)-1-hydroxypropan-2-yl)-2,2-difluoro-4-(naphthalen-2- yl)butanamide145 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- A*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-4-(naphthalen-2-yl)-2-oxobutanamide 146N-((1R,2R)-1-(3-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(6-chloronaphthalen-2-yl)-2,2-difluoroacetamide 147N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-4-(naphthalen-2-yl)-2-oxobutanamide 148(E)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)-4-(naphthalen-2-yl)butanamide 149N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 150 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 1512-(6-chloronaphthalen-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 152N-((1R,2R)-1-(3-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 153(E)-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-(hydroxyimino)acetamide 154N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- B*hydroxypropan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-oxobutanamide 155(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-(hydroxyimino)acetamide 1562-(7-chloronaphthalen-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 157N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 158(E)-2-(6-chloronaphthalen-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide 159N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 160N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 161N-((1R,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6- Ayl)-1-hydroxypropan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 162N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- A*hydroxypropan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 163N-((1R,2R)-1-(3-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 164(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4- A*cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-2-(hydroxyimino)-4-(naphthalen-2-yl)butanamide 165N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanamide 166N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanamide 1672,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanamide 168N-((1S,2R)-1-(3-chloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-1- B*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide 169(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4- A*cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2-(hydroxyimino)acetamide 170N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- B*hydroxypropan-2-yl)-4-(naphthalen-2-yl)-2-oxobutanamide 171N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- Ahydroxypropan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide 172N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(6-chloronaphthalen-2-yl)-2-oxoacetamide 173(E)-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(6-chloronaphthalen-2-yl)-2-(hydroxyimino)acetamide 174N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-oxoacetamide 175N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5-fluoropyridin-2-yl)phenyl)-2-oxoacetamide 176N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5-fluoropyridin-2-yl)phenyl)-2-oxoacetamide 177(E)-N-((1R,2R)-1-(3-chloro-4-((tetrahydro-2H-pyran-4- Ayl)oxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-(hydroxyimino)acetamide 178N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(5-fluoropyridin-2-yl)phenyl)acetamide 179N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(5-fluoropyridin-2-yl)phenyl)acetamide 180N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(4-fluorophenyl)thiophen-2-yl)acetamide 181(Z)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy- A3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-(hydroxyimino)acetamide 182N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(pyridin-2-yl)phenyl)acetamide 1832,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5-fluoropyridin-2-yl)phenyl)acetamide 184(E)-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5-fluoropyridin-2-yl)phenyl)-2-(hydroxyimino)acetamide 1852-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydro- B*[1,4]dioxino[2,3-b]pyridin-7-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 186N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(pyridin-2-yl)phenyl)acetamide 1872,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide 188 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- A*dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(6-chloronaphthalen-2-yl)-2-oxoacetamide 189N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5-fluoropyridin-2-yl)phenyl)-2-oxoacetamide 190(E)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy- A*3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5-fluoropyridin-2-yl)phenyl)-2-(hydroxyimino)acetamide 191(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(6-chloronaphthalen-2-yl)-2-(hydroxyimino)acetamide 1922-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(3-chloro-4- A*(2-hydroxy-2-methylpropoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide 193N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide 194N-((1R,2R)-1-(3-chloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 195N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(pyridin-2- yl)phenyl)acetamide196 2,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-B* 6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(imidazo[1,2-a]pyridin-2-yl)acetamide 197N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(3-(4-fluorophenoxy)phenyl)-2-oxoacetamide 198N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide 199N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(imidazo[1,2-a]pyridin-2-yl)acetamide 200N-((2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(piperidin-1-yl)phenyl)acetamide 201N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(3-(4-fluorophenoxy)phenyl)acetamide 202N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(1-methyl-1H-indazol-5-yl)phenyl)acetamide 203N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-(4-fluorophenoxy)phenyl)-2-oxoacetamide 204N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide 205N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-methyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 206N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(3-(4-fluorophenoxy)phenyl)acetamide 207N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-methyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 208N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 209N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(naphthalen-2-yl)-2-oxoacetamide 2102,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-(4-fluorophenoxy)phenyl)acetamide 211N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(2-(4-fluorophenyl)thiazol-4-yl)acetamide 212N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(1-methyl-1H-indazol-5-yl)phenyl)acetamide 213N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(2-(4-fluorophenyl)thiazol-4-yl)acetamide 214N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(pyridin-2- yl)phenyl)acetamide215 N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorophenyl)thiazol-5-yl)-2-oxoacetamide 216N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-methyl-1H-indazol-5-yl)-2-oxoacetamide 217N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-methyl-1H-indazol-5-yl)-2-oxoacetamide 218N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(4-fluorophenyl)thiophen-2-yl)acetamide 219N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-oxoacetamide 220N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-methyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 2212,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A*6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorophenyl)thiazol-4-yl)acetamide 222N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(2-(4-fluorophenyl)thiazol-5-yl)acetamide 223N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4-(1-methyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 224N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2-(1-methyl-1H-indazol-5-yl)-2-oxoacetamide 225N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2-(2-chlorobenzo[b]thiophen-5-yl)-2-oxoacetamide 226N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- B*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorophenyl)thiazol-4-yl)-2-oxoacetamide 227N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-oxo-2-(4-(piperidin-1-yl)phenyl)acetamide 228N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(pyridin-2-yl)phenyl)acetamide 229N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorophenyl)thiazol-4-yl)-2-oxoacetamide 230N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-oxoacetamide 231N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(piperidin-1-yl)phenyl)acetamide 232N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(1-methyl-1H-indazol-6-yl)phenyl)acetamide 2332-(benzo[b]thiophen-5-yl)-N-((1R,2R)-1-(3-chloro-4- Acyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 234N-((1R,2R)-1-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 235N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(1-methyl-1H-indazol-6-yl)phenyl)acetamide 2362,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-methyl-1H-indazol-6-yl)phenyl)acetamide 237N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4-(2-methyl-2H-indazol-6-yl)phenyl)acetamide 238N-((2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(3-(piperidin-1-yl)phenyl)acetamide 2392,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- A6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)acetamide 240N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-methyl-2H-indazol-5-yl)phenyl)-2-oxoacetamide 241N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(4-fluorophenoxy)phenyl)-2-oxoacetamide 242N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(6-chlorobenzo[b]thiophen-2-yl)-2-oxoacetamide 243N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-methyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 244N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-methyl-1H-indazol-6-yl)-2-oxoacetamide 245N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- A*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-methyl-1H-indazol-6-yl)-2-oxoacetamide 246N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-methyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 247N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(6-(4-fluorophenyl)pyridin-3-yl)acetamide 248N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(3-(4-fluorophenoxy)phenyl)-2-oxoacetamide 249N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(3-(4-fluorophenoxy)phenyl)-2-oxoacetamide 250N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-3-yl)-2-oxoacetamide 251N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-3-yl)-2-oxoacetamide 252N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2-(4-(4-fluorophenyl)piperazin-1-yl)-2-oxoacetamide 253N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- Ahydroxypropan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2- oxoacetamide254 N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(4-fluorophenyl)piperazin-1-yl)-2-oxoacetamide 2552-(4′-(tert-butyl)-[1,1′-biphenyl]-4-yl)-N-((1R,2R)-1-(3-chloro-4- Acyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 256N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 257N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-isopropyl-2H-indazol-6-yl)phenyl)-2-oxoacetamide 258N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 259N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-isopropyl-2H-indazol-5-yl)phenyl)-2-oxoacetamide 260N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(4-fluorophenyl)pyridin-2-yl)acetamide 261N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A*(pyrrolidin-1-yl)propan-2-yl)-2-(3-(1-methyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 262N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B*(pyrrolidin-1-yl)propan-2-yl)-2-(4-(4-fluorophenyl)piperazin-1-yl)-2-oxoacetamide 263N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-chlorobenzo[b]thiophen-5-yl)phenyl)-2-oxoacetamide 264N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)pyridin-2-yl)-2-oxoacetamide 265N-((1R,2R)-1-(4-cyclopropoxy-3-(trifluoromethyl)phenyl)-1- B*hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 266N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-indol-5-yl)phenyl)-2-oxoacetamide 2672-(4′-chloro-[1,1′biphenyl]-4-yl)-N-((1R,2R)-1-(2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 268N-((1R,2R)-1-(5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 269N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-indol-5-yl)phenyl)-2-oxoacetamide 270N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-chloro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 271N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-benzo[d]imidazol-5-yl)phenyl)-2-oxoacetamide 2722-(4′-chloro-[1,1′biphenyl]-4-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 273N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(pyrrolidin-1-yl)phenyl)acetamide 274N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)acetamide 2752-(4-(1-cyclopropyl-1H-indazol-5-yl)phenyl)-N-((1R,2R)-1-(8- Afluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 276N-((1R,2R)-1-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-cyclopropyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 277N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-cyclopropyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 278N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4-(1-cyclopropyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 279N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- Ahydroxypropan-2-yl)-2-(4-(1-methyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 2802-(4-(benzo[d]isoxazol-6-yl)phenyl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 281N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-cyclopropyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 2822-(4-(1-cyclopropyl-1H-indazol-6-yl)phenyl)-N-((1R,2R)-1-(8- Afluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 283N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4-(1-cyclopropyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 284N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-cyclopropyl-2H-indazol-6-yl)phenyl)-2-oxoacetamide 285N-((1R,2R)-3-(azetidin-1-yl)-1-(8-chloro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4-(1-cyclopropyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 2862-(4′-fluoro-[1,1′-biphenyl]-4-yl)-N-((1R,2R)-1-hydroxy-3- B(pyrrolidin-1-yl)-1-(8-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-2-yl)-2-oxoacetamide 287N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(6-(4-fluorophenyl)pyridin-3-yl)-2-oxoacetamide 288N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4-fluorobenzyl)-1H-indazol-5-yl)-2-oxoacetamide 289N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4-fluorobenzyl)-1H-indazol-5-yl)-2-oxoacetamide 2902-(4-(benzo[d]isoxazol-5-yl)phenyl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 291N-((1R,2R)-1-(4-(tert-butoxy)-3-chlorophenyl)-1-hydroxy-3- B(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 2922-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3- Afluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2- oxoacetamide293 N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4′-(tert-butyl)-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 2942-(4′-(tert-butyl)-[1,1′-biphenyl]-4-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 295N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-2′-methyl-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 2962-(4-(benzo[d]thiazol-5-yl)phenyl)-N-((1R,2R)-1-(3-chloro-4- Acyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 2972-(4-(benzo[d]thiazol-6-yl)phenyl)-N-((1R,2R)-1-(3-chloro-4- Acyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 298N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-2-methyl-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 299N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-2-methyl-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 300N-((1R,2R)-3-(azetidin-1-yl)-1-(8-chloro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 301N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-cyano-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 3022-(8-bromodibenzo[b,d]furan-2-yl)-N-((1R,2R)-1-(3-chloro-4- Acyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 303N-[(1R,2R)-2-(3-chloro-4-cyclopropoxyphenyl)-2-hydroxy-1- A(pyrrolidinylmethyl)ethyl]-2-[4-(4-fluorophenyl)phenyl]acetamide 304N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorobenzyl)-2H-indazol-5-yl)-2-oxoacetamide 305N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorobenzyl)-2H-indazol-5-yl)-2-oxoacetamide 306N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-1H-indazol-6-yl)-2-oxoacetamide 307N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-1H-indazol-6-yl)-2-oxoacetamide 3082-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 309N-((1R,2R)-1-(3-chloro-4-(cyclopentyloxy)phenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 310N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-isopropyl-3-methyl-2H-indazol-5-yl)phenyl)-2-oxoacetamide 311N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(2-isopropyl-2H-indazol-5-yl)-2-oxoacetamide 312N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2-isopropyl-2H-indazol-6-yl)-2-oxoacetamide 313N-((1R,2R)-1-(3-chloro-4-cyclobutoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 314N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-3-methyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 3152-(4′-fluoro-2′-methyl-[1,1′-biphenyl]-4-yl)-N-((1R,2R)-1-(8-fluoro- A2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 316N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(2-isopropyl-2H-indazol-6-yl)-2-oxoacetamide 317N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-3-methyl-1H-indazol-5-yl)-2-oxoacetamide 318N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1,3-dimethyl-1H-indazol-5-yl)phenyl)-2-oxoacetamide 319N-((1R,2R)-1-(benzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1- Ayl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 320N-((1R,2R)-1-(3-chloro-4-(cyclopropylthio)phenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 321N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-1H-indazol-5-yl)-2-oxoacetamide 3222-(4-(1,3-dimethyl-1H-indazol-5-yl)phenyl)-N-((1R,2R)-1-(8-fluoro- A2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 323N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-1H-indol-5-yl)-2-oxoacetamide 324N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-1H-indol-5-yl)-2-oxoacetamide 325N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-morpholinophenyl)-2-oxoacetamide 326(S)-N-(1-(3-chloro-4-cyclopropoxyphenyl)-3-(pyrrolidin-1- Byl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 327N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- Ahydroxypropan-2-yl)-2-oxo-2-(4-(pyrrolidin-1-yl)phenyl)acetamide 328N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-4-(6-chloronaphthalen-2-yl)-2,2-difluorobutanamide 329N-((1R,2R)-1-(3-chloro-4-(vinyloxy)phenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 330N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-2-oxoacetamide 331N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-1H-indol-6-yl)-2-oxoacetamide 332N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-isopropyl-1H-indol-6-yl)-2-oxoacetamide 333N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1- Ayl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 334N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-3-methyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 335N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-isopropyl-3-methyl-2H-indazol-6-yl)phenyl)-2-oxoacetamide 336N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2-isopropyl-3-methyl-2H-indazol-6-yl)phenyl)-2-oxoacetamide 337N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-3-methyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 338N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1- Ahydroxypropan-2-yl)-2-(6-chlorobenzo[b]thiophen-2-yl)-2- oxoacetamide339 N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-isopropyl-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 340N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1,3-dimethyl-1H-indazol-6-yl)phenyl)-2-oxoacetamide 3412-(4-(1,3-dimethyl-1H-indazol-6-yl)phenyl)-N-((1R,2R)-1-(8-fluoro- A2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 3422-(4-(2,3-dimethyl-2H-indazol-6-yl)phenyl)-N-((1R,2R)-1-(8-fluoro- A2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 343N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(pyrrolidin-1-yl)phenyl)acetamide 344N-((1R,2R)-1-(3-fluoro-4-isopropoxy-5-methoxyphenyl)-1-hydroxy- A3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 345N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-indol-6-yl)phenyl)-2-oxoacetamide 346N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-indol-6-yl)phenyl)-2-oxoacetamide 347N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(2,3-dimethyl-2H-indazol-6-yl)phenyl)-2-oxoacetamide 3482-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(3-fluoro-4- Bisopropoxy-5-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 349N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-cyclopropyl-1H-pyrazol-3-yl)phenyl)-2-oxoacetamide 3502-(4-(1-cyclopropyl-1H-pyrazol-3-yl)phenyl)-N-((1R,2R)-1-(8- Afluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 351N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-pyrazol-3-yl)phenyl)-2-oxoacetamide 352N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-pyrazol-3-yl)phenyl)-2-oxoacetamide 353N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-oxoacetamide 354N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorophenyl)-2H-indazol-5-yl)-2-oxoacetamide 355N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)acetamide 356N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 357N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-isopropyl-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 358N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 3592-(4-(5-chlorothiophen-2-yl)phenyl)-N-((1R,2R)-1-(4-cyclopropoxy- A3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 3602-(4-(5-chlorothiophen-2-yl)phenyl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 361N-((1R,2R)-1-(3-fluoro-5-isopropoxy-4-methoxyphenyl)-1-hydroxy- B3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 362 N-((1R,2R)-1-(8-fluoro-3,3-dimethyl-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 363N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5-chlorothiophen-2-yl)phenyl)-2-oxoacetamide 3642-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(3-fluoro-5- Bisopropoxy-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 365N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(6-chlorobenzofuran-2-yl)-2-oxoacetamide 366 2-(6-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3-A dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 367N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- ntdihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-oxo-2-(4-(pyrrolidin-1-yl)phenyl)acetamide 368N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-morpholinophenyl)-2- oxoacetamide 369N-((1R,2R)-3-(azetidin-1-yl)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(4-morpholinophenyl)-2-oxoacetamide 370N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-cyclopropyl-[1,1′-biphenyl]-4-yl)-2-oxoacetamide 3712-(4′-cyclopropyl-[1,1′-biphenyl]-4-yl)-N-((1R,2R)-1-(8-fluoro-2,3- Adihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 372N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)acetamide 373N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)acetamide 374N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1- Byl)propan-2-yl)-2-(4-morpholinophenyl)-2-oxoacetamide 3752-(4-(azetidin-1-yl)phenyl)-N-((1R,2R)-1-(3-chloro-4- Bcyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 376N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-fluorophenyl)-2-oxoacetamide 3772-(benzo[b]thiophen-2-yl)-N-((1R,2R)-1-(3-chloro-4- Acyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide 378N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4-ethynylphenyl)-2-oxoacetamide 379N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- Ahydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-fluorophenyl)-2-oxoacetamide 380N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- B(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4-fluorophenyl)piperidin-4-yl)-2-oxoacetamide 381N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxy-3-fluorophenyl)-1- Ahydroxypropan-2-yl)-2-(6-chlorobenzo[b]thiophen-2-yl)-2- oxoacetamide382 N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- A(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-N-methyl-2-oxoacetamide 3832-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3- Afluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-N-methyl-2-oxoacetamide

TABLE 3 The data provided is the IC₅₀ (nM) generated from Assay 1,except as otherwise noted by *, which is % inhibition, also generatedfrom Assay 1. Ex Structure Name Data 384

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5- chlorobenzo[b]thiophen-2-yl)-2-oxoacetamide A 385

2-(4-(1H-1,2,3-triazol-1-yl)phenyl)-N- ((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide B 386

2-(6-chlorobenzo[b]thiophen-2-yl)-N- ((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-oxoacetamide B 387

N-((1R,2R)-3-(azetidin-1-yl)-1-(4- cyclopropoxy-3-fluorophenyl)-1-hydroxypropan-2-yl)-2-(5- chlorobenzo[b]thiophen-2-yl)-2- oxoacetamide A388

2-(benzo[b]thiophen-2-yl)-N- ((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-oxoacetamide A 389

N-((1R,2R)-1-(4-chlorophenyl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2- oxoacetamide B 390

N-((1R,2R)-1-(4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2- difluoro-4-(naphthalen-2-yl)butanamide A 391

2-(5-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-oxoacetamide A 392

2-(4-(5-chlorothiophen-2-yl)phenyl)- N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide A 393

2-(4-(5-chlorothiophen-2-yl)phenyl)- N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide A 394

N-((1R,2R)-1-(4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4- yl)acetamide A 395

N-((1R,2R)-1-(4-cyclopropoxy-3- fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4- cyclopropylphenyl)-2-oxoacetamide A396

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(5- chlorothiophen-2-yl)phenyl)-2,2-difluoroacetamide A 397

2-(4-(5-chlorothiophen-2-yl)phenyl)- N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide A 398

2-(4-(5-chlorothiophen-2-yl)phenyl)-2,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan- 2-yl)acetamide A 399

2-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-oxoacetamide A 400

2-(4-(1H-pyrazol-1-yl)phenyl)-N- ((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide A 401

N-((1R,2R)-1-(4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4- ethynylphenyl)-2-oxoacetamide B 402

4-(6-chloronaphthalen-2-yl)-N- ((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2,2-difluorobutanamide B 403

2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-N- ((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide A 404

N-((1R,2R)-1-(4-cyclopropoxy-3- fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-N-methyl- 2-oxoacetamide A 405

2-(6-chlorobenzo[b]thiophen-2-yl)-N- ((1R,2R)-1-(4-(difluoromethoxy)phenyl)-1-hydroxy- 3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide B 406

(E)-N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6- fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide  A* 407

N-((1R,2R)-3-(azetidin-1-yl)-1-(4- cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-2-(4′-fluoro-[1,1′- biphenyl]-4-yl)-2-oxoacetamident 408

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(isoxazolidin-2-yl)propan-2-yl)-2-(4′- fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide nt 409

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(isoxazolidin-2-yl)propan-2-yl)-2-(6- chlorobenzo[b]thiophen-2-yl)-2-oxoacetamide nt 410

2-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-oxoacetamide nt 411

4-(6-chloronaphthalen-2-yl)-N- ((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2,2-difluorobutanamide nt 412

N-((1R,2R)-1-(4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4- ethynylphenyl)-2-oxoacetamide nt 413

2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-N- ((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide nt 414

2-(4-(1H-pyrazol-1-yl)phenyl)-N- ((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide nt 415

2-(benzo[b]thiophen-2-yl)-N- ((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-oxoacetamide nt 416

2-(5′-chloro-[2,2′-bithiophen]-5-yl)-N- ((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2- oxoacetamident 417

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2′,4′-difluoro-[1,1′-biphenyl]-4-yl)-2- oxoacetamide nt 418

2-(3-chloropyrrolo[1,2-b]pyridazin-6- yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 419

2-(7-chloroimidazo[1,2-a]pyridin-2- yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 420

N-((1R,2R)-1-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2,2-difluoro-2-(6-(trifluoromethyl)furo[3,2-c]pyridin-2- yl)acetamide nt 421

2-(6-chlorofuro[3,2-b]pyridin-2-yl)-N- ((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 422

N-((1R,2R)-1-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2,2-difluoro-2-(2-(trifluoromethyl)furo[2,3-d]pyrimidin- 6-yl)acetamide nt 423

2-(5-chlorothieno[3,2-b]furan-2-yl)-N- ((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 424

2-(5-chlorothieno[2,3-d]oxazol-2-yl)- N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 425

2-(2-chlorofuro[2,3-d]thiazol-5-yl)-N- ((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 426

3-(3-chlorobenzyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluorobut-3-enamide nt 427

2-(5-chlorobenzofuran-2-yl)-N- ((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(2,2,5,5-tetradeuteropyrrolidin-1-yl)propan-2- yl)-2,2-difluoroacetamide nt 428

N-((1R,2R)-1-(3-chloro-4-((4- hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2- difluoroacetamide nt 429

2-(5-chloro-2,3-dihydro-1H-inden-2- yl)-N-((1R,2R)-1-(3-chloro-4-((4-hydroxytetrahydro-2H-pyran-4- yl)methoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2- difluoroacetamide nt 430

2-(5-chlorobenzofuran-2-yl)-2,2- difluoro-N-((1R,2R)-1-hydroxy-1-(4-((4-hydroxytetrahydro-2H-pyran-4- yl)methoxy)phenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide nt 431

N-((1R,2R)-1-(4-chloro-3-((4- hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2- difluoroacetamide nt 432

2-(5-chlorobenzofuran-2-yl)-2,2- difluoro-N-((1R,2R)-1-hydroxy-1-(2-isopropoxypyridin-4-yl)-3-(pyrrolidin- 1-yl)propan-2-yl)acetamide nt 433

2-(5-chlorobenzofuran-2-yl)-N- ((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1- yl)propan-2-yl)-2-oxoacetamide nt 434

(E)-2-(5-chlorobenzofuran-2-yl)-N- ((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1- yl)propan-2-yl)-2-(hydroxyimino)acetamide nt 435

2-(5-chloro-2,3-dihydro-1H-inden-2- yl)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy- 3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide nt 436

(E)-2-(5-chloro-2,3-dihydro-1H-inden- 2-yl)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy- 3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide nt 437

2-(5-chlorobenzofuran-2-yl)-2,2- difluoro-N-((1R,2R)-1-hydroxy-1-(6-((4-hydroxytetrahydro-2H-pyran-4- yl)methoxy)pyridin-3-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide nt 438

N-((1R,2R)-1-(6-cyclopropoxypyridin- 3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen- 2-yl)-2-oxobutanamide nt 439

(E)-N-((1R,2R)-1-(6- cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6- fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide nt 440

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6- fluoronaphthalen-2-yl)-2-oxobutanamide nt 442

N-((1R,2R)-1-(6-cyclopropoxypyridin- 3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5- (trifluoromethyl)benzofuran-2-yl)acetamide nt 443

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2- (5-(trifluoromethyl)benzofuran-2-yl)acetamide nt 444

(E)-N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2- (hydroxyimino)-2-(5-(trifluoromethyl)benzofuran-2- yl)acetamide nt 445

(E)-N-((1R,2R)-1-(6- cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2- (hydroxyimino)-2-(5-(trifluoromethyl)benzofuran-2- yl)acetamide nt 446

N-((1R,2R)-1-(6-cyclopropoxypyridin- 3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(5- (trifluoromethyl)benzofuran-2- yl)acetamident 447

2-(5-chlorobenzofuran-2-yl)-N- ((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- formamido-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 448

(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2- (hydroxyimino)acetamide nt 449

(E)-N-((1R,2R)-3-(azetidin-1-yl)-1-(3- chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-2-(5- chlorobenzofuran-2-yl)-2-(methoxyimino)acetamide nt 450

2-(5-chlorobenzofuran-2-yl)-N- ((1R,2R)-1-(3,5-dichloro-4-cyclopropoxyphenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide nt 451

N-((1R,2R)-3-(azetidin-1-yl)-1-(3- chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-2,2-difluoro-4- (6-fluoronaphthalen-2-yl)butanamident 452

(E)-N-((1R,2R)-1-(8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-4-(6-fluoronaphthalen-2-yl)-2-(methoxyimino)butanamide nt 453

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2- (5-(trifluoromethyl)benzofuran-2-yl)acetamide nt 454

(E)-N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2- (hydroxyimino)-2-(5-(trifluoromethyl)benzofuran-2- yl)acetamide nt 455

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(5- chlorobenzo[b]thiophen-2-yl)-2,2-difluorobutanamide nt 456

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(3-(pyridin-2-yloxy)phenyl)acetamide nt 457

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-((1-methyl-1H-indazol-6-yl)oxy)phenyl)- 2-oxoacetamide nt 458

N-((1R,2R)-1-(8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-(3-((1-methyl-1H-indazol-6-yl)oxy)phenyl)-2-oxoacetamide nt 459

N-((1R,2R)-1-(8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-(1-(4-fluorophenyl)-1H-imidazol-4-yl)-2-oxoacetamide nt 460

2-(1-(6-chloronaphthalen-2-yl)-1H- pyrazol-3-yl)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan- 2-yl)-2-oxoacetamide nt 461

2-(1-(6-chloronaphthalen-2-yl)-1H- pyrazol-4-yl)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan- 2-yl)-2-oxoacetamide nt 462

N-((1R,2R)-1-(8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4-fluorophenyl)-1H-pyrazol- 4-yl)-2-oxoacetamide nt 463

2-(4-(6-chloronaphthalen-2-yl)-1- methyl-1H-imidazol-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-oxoacetamide nt 464

N-((1R,2R)-1-(8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)-2-(4-(4-fluorophenyl)-1-methyl-1H-imidazol-2-yl)-2-oxoacetamide nt 465

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4- fluorophenoxy)pyridin-4-yl)-2-oxoacetamide nt 466

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2- difluoro-2-(2-(4-fluorophenoxy)pyridin-4-yl)acetamide nt 467

N-((1R,2R,3S)-1-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)butan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2- oxoacetamide nt 468

N-((1R,2R)-1-(3-chloro-4- (difluoromethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(6- chlorobenzo[b]thiophen-2-yl)-2-oxoacetamide nt 469

2-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4′-fluoro-[1,1′-biphenyl]- 4-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide nt 470

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(2-oxopyrrolidin-1-yl)propan-2-yl)-2-(4′- fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide nt 471

N-((1R,2R)-1-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(2-oxopyrrolidin-1- yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide nt 472

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4- fluorophenyl)-1H-pyrazol-4-yl)-2-oxoacetamide nt 473

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrazolidin-1-yl)propan-2-yl)-2-(4′- fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide nt 474

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrazolidin-1-yl)propan-2-yl)-2-(6- chlorobenzo[b]thiophen-2-yl)-2-oxoacetamide nt 475

N-((1R,2R)-1-(4-cyclopropoxy-3- fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(prop-1-yn-1-yl)phenyl)acetamide nt 476

2-(5′-chloro-[2,2′-bithiophen]-5-yl)-N- ((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)-2- oxoacetamident 477

N-((1R,2R)-1-(3-chloro-4- cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(6-(5-chlorothiophen-2-yl)pyridin-3-yl)-2- oxoacetamide nt 478

2-(6-(5-chlorothiophen-2-yl)pyridin-3-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3- fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2- oxoacetamide nt

Sandhoff Disease Mouse Model

The murine model of Sandhoff disease is a knock out (KO) of the HEXBgene, which codes for beta-hexosaminidase in mice, as it does in humans.This KO mouse displays a phenotype closely resembling that seen inhumans, although at a more advanced age, compared to humans. At ˜3months of age, the animals develop tremor and increased limb tone, whichis worse in the hind legs. These manifestations become progressivelymore severe until 4-5 months of age, when the animals become moribundand rapidly lose weight. The motor phenotype has been quantified byactivity monitor, bar-crossing, and inverted screen tests (Jayakumar Met al Blood 2001, 97, 327-329; Cachon-Gonzalez et al PNAS 2006, 103(27),1037-10378). Histologically, the mouse neurons appear to be distended bylysosomal storage material, and signs of neuroinflammation are present.Biochemically, levels of beta-hexosaminidase are absent, andaccumulations of gangliosides GM2, GA2, as well as sialic acid, can bedemonstrated (Cachon-Gonzalez et al 2006; Arthur et al Neurochem Res2013, DOI 10.1007/s11064-013-0992-5).

To evaluate the potential efficacy of different BioMarin substratereduction compounds in Sandhoff disease, homozygous male mice are matedwith heterozygous females. All pups (approximately 50% KO and 50% het)in a litter are treated by daily IP or SC injection with the same test(or control) article for 14 days, beginning at 3 days old. The chosenroute of administration is determined based onpharmacokinetic/pharmacodynamic properties of the compound to be tested.At the end of the dosing period, pups are deeply anesthetized usingisoflurane through nose cones (4% for induction and 1.5% formaintenance), blood is collected by cardiac puncture method, then themice are euthanized. Brains and livers are collected and snap frozen.These tissues are used for analysis of experimental endpoints (GM2 andsialic acid in brain, GA2 and sialic acid in liver). An additionaltissue sample (tail tip or toe) is collected and snap frozen, then sentfor genotyping.

I(f) tested compounds are found which have a marked effect on theexperimental endpoints, an additional experiment is performed looking ateffects on activity, inverted screen, and bar crossing tests, as well asaverage survival time, compared to vehicle-treated mice.

Polycystic Kidney Disease Mouse Model

To jck mice is administered a compound of the invention ad libitum infood (standard chow) from 26-64 days of age. Control jck mice are fed acontrol diet from 26-64 days of age. At 63 days of age, the animals aretransferred to metabolic cages for 24 hour urine collection. At 64 daysof age, animals are sacrificed, weighed, and blood is collected by heartpuncture for serum isolation. Kidneys are isolated, bisected, andweighed and half of each kidney is fixed in 4% paraformaldehyde in PBSovernight for paraffin embedding and hematoxylin and eosin staining.Kidney weight to body weight ratio is used to determine activity of thecompound. Cyst volume is measured by quantitating the percentage ofcystic area in histological sections of kidneys from the treated andcontrol animals and multiplied by the kidney/body weight ratio. Kidneyfunction is assessed by measuring blood urea nitrogen (BUN) levels inserum samples derived from animals at sacrifice. BUN levels are elevatedin untreated controls while the treated animals demonstrated asignificant reduction of BUN levels.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdescription. It should be understood, however, that the description andthe specific examples, while indicating specific embodiments, are givenby way of illustration only, since various changes and modificationswithin the spirit and scope of the present description will becomeapparent from this detailed description.

All publications including patents, patent applications and publishedpatent applications cited herein are hereby incorporated by referencefor all purposes.

1. A compound of Formula I:

wherein R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);X¹ is alkylene, alkenylene, or cycloalkylene; R^(1a) is alkyl,heterocycloalkyl, aryl or heteroaryl each of which is optionallysubstituted with 1, 2, or 3 R⁷ groups; wherein when R^(1a) is phenyl,R^(1a) is substituted with 1, 2, or 3 R⁷ groups; R² and R³ together withthe nitrogen to which they are attached form a 3-10 memberedheterocycloalkyl ring, optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 R⁸; R⁴ is aryl or heteroaryl each of which is optionallysubstituted with 1, 2, 3, or 4 R⁹ groups; R⁵ is —OH, and R^(5a) ishydrogen; R⁶ and R^(6a) are halo; R¹ and R^(6a) are deuterium; or R⁶ andR^(6a) together with the carbon to which they are attached form C(═NOH)or C(O); each R⁷, when present, is independently nitro, cyano, amino,alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl,hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, heterocycloalkyl,phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, orheteroaryloxy; where the phenyl and the heteroaryl, either alone or aspart of another group, are independently optionally substituted with 1,2 or 3 R^(7a); each R^(7a), when present, is independently selected fromcyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;each R⁸, when present, is independently deuterium, amino, alkylamino,dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl; ortwo R⁸ together with the carbon to which they are attached form C(O);each R⁹, when present, is independently cyano, nitro, amino, alkylamino,dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy,hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy,cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy,heteocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and thephenyl, either alone or as part of another group, are independentlyoptionally substituted with 1 or 2 R^(9a); each R^(9a), when present, isindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl,haloalkoxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; and R¹²is hydrogen or C₁₋₅ alkyl; optionally a tautomer, a single stereoisomeror mixture of stereoisomers thereof and additionally optionally apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein the compound of Formula I is according to Formula I(b) orFormula I(c):

optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof.
 3. (canceled)
 4. The compound of claim 1,wherein R² and R³ together with the nitrogen to which they are attachedform a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 memberedbicyclic heterocycloalkyl; each of which is optionally substituted with1 or 2 R⁸; optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof.
 5. (canceled)
 6. The compound of claim 1,wherein R⁴ is aryl which is optionally substituted with 1, 2, or 3 R⁹groups; optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof.
 7. The compound of claim 6, wherein each R⁹,when present, is independently halo, alkoxy, alkenyloxy,hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy,cycloalkylalkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof.
 8. (canceled)
 9. The compound of claim 1,wherein R⁴ is heteroaryl which is optionally substituted with 1, 2, or 3R⁹ groups; optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof.
 10. The compound of claim 9, wherein R⁴ is2,3-dihydrobenzo[b][1,4]dioxin-6-yl optionally substituted with a halo;optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof. 11-12. (canceled)
 13. The compound of claim 1,wherein X¹ is C₁₋₃ alkylene; optionally as a tautomer, a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof.
 14. Thecompound of claim 1, wherein R^(1a) is aryl optionally substituted with1, 2, or 3 R⁷ groups; wherein when R^(1a) is phenyl, R^(1a) issubstituted with 1, 2, or 3 R⁷ groups; optionally as a tautomer, asingle stereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof.
 15. Thecompound of claim 14, wherein R^(1a) is phenyl substituted with 1 R⁷group, wherein each R⁷ is independently phenyl, heterocycloalkyl, orheteroaryl; where the phenyl and the heteroaryl are independentlyoptionally substituted with 1 or 2 R^(7a); optionally as a tautomer, asingle stereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof.
 16. Thecompound of claim 1, wherein R^(1a) is heteroaryl optionally substitutedwith 1, 2, or 3 R⁷ groups; optionally as a tautomer, a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof.
 17. Thecompound of claim 16, wherein R^(1a) is heteroaryl optionallysubstituted with 1 or 2 R⁷ groups, wherein each R⁷, when present, isindependently halo, alkyl, cycloalkyl, heterocycloalkyl, phenyl,phenylalkyl, or heteroaryl; where the phenyl and the heteroaryl, eitheralone or as part of another group, are independently optionallysubstituted with 1 R^(7a); optionally as a tautomer, a singlestereoisomer or mixture of stereoisomers thereof and additionallyoptionally as a pharmaceutically acceptable salt thereof.
 18. Thecompound of claim 1, wherein R⁶ and R^(6a) together with the carbon towhich they are attached form C(O) or C(═NOH); optionally as a tautomer,a single stereoisomer or mixture of stereoisomers thereof andadditionally optionally as a pharmaceutically acceptable salt thereof.19. (canceled)
 20. The compound of claim 1, wherein R⁶ and R^(6a) arehalo; optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof.
 21. (canceled)
 22. The compound of claim 1wherein: R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or —C(O)C(R⁶)(R^(6a))—X¹—R^(1a);X¹ is alkylene, alkenylene, or cycloalkylene; R^(1a) is alkyl,heterocycloalkyl, aryl or heteroaryl each of which is optionallysubstituted with 1, 2, or 3 R⁷ groups; wherein when R^(1a) is phenyl,R^(1a) is substituted with 1, 2, or 3 R⁷ groups; R² and R³ together withthe nitrogen to which they are attached form a 4-5 membered monocyclicheterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; eachof which is optionally substituted with 1 or 2 R⁸; R⁴ is aryl orheteroaryl each of which is optionally substituted with 1, 2, or 3 R⁹groups; R⁵ is —OH, and R^(5a) is hydrogen; R⁶ and R^(6a) are halo; or R⁶and R^(6a) together with the carbon to which they are attached formC(═NOH) or C(O); each R⁷, when present, is independently nitro, cyano,halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, orheteroaryloxy; where the phenyl and the heteroaryl, either alone or aspart of another group, are independently optionally substituted with 1,2 or 3 R^(7a), each R^(7a), when present, is independently selected fromcyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;each R⁸, when present, is independently amino, alkylamino, dialkylamino,alkyl, halo, or cycloalkyl; or two R⁸ together with the carbon to whichthey are attached form C(O); each R⁹, when present, is independentlycyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl,hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy,cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl,heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where theheterocycloalkyl and the phenyl, either alone or as part of anothergroup, are independently optionally substituted with 1 or 2 R^(9a); eachR^(9a), when present, is independently selected from alkyl, hydroxy,alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino,and dialkylamino; and R¹² is hydrogen or CH₃; optionally a tautomer, asingle stereoisomer or mixture of stereoisomers thereof and additionallyoptionally a pharmaceutically acceptable salt thereof.
 23. The compoundof claim 1 wherein: R¹ is —C(O)C(R⁶)(R^(6a))R^(1a) or—C(O)C(R⁶)(R^(6a))—X¹—R^(1a); X¹ is alkylene; R^(1a) isheterocycloalkyl, aryl or heteroaryl each of which is optionallysubstituted with 1, 2, or 3 R⁷ groups; wherein when R^(1a) is phenyl,R^(1a) is substituted with 1, 2, or 3 R⁷ groups; R² and R³ together withthe nitrogen to which they are attached form a 4-5 membered monocyclicheterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; eachof which is optionally substituted with 1 or 2 R⁸; R⁴ is aryl orheteroaryl each of which is optionally substituted with 1, 2, or 3 R⁹groups; R⁵ is —OH, and R³ is hydrogen; R⁶ and R^(6a) are halo; or R⁶ andR^(6a) together with the carbon to which they are attached form or C(o);each R⁷, when present, is independently nitro, cyano, halo, haloalkyl,alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl,phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy;where the phenyl and the heteroaryl, either alone or as part of anothergroup, are independently optionally substituted with 1, 2 or 3 R⁷, eachR^(7a), when present, is independently selected from cyano, halo, alkyl,alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; each R⁸, when present,is independently amino, alkylamino, dialkylamino, alkyl, or halo; eachR⁹, when present, is independently amino, alkylamino, dialkylamino,halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy,haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy,heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, orphenyl; where the heterocycloalkyl and the phenyl, either alone or aspart of another group, are independently optionally substituted with 1or 2 R^(9a); each R^(9a), when present, is independently selected fromalkyl and halo; and R¹² is hydrogen or CH₃; optionally a tautomer, asingle stereoisomer or mixture of stereoisomers thereof and additionallyoptionally a pharmaceutically acceptable salt thereof. 24-28. (canceled)29. A compound selected from the group consisting of:2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(S-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzo[b]thiophen-2-yl)-2,2-difluoro-N-((2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1S,2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1R,2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(5-chlorobenzo[d]thiazol-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1R,2R)-1-(2-fluoro-5-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1S,2R)-1-(2-fluoro-5-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(5-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(2,3-dihydro-1H-inden-2-yl)-2,2-difluoro-N-((1S,2R)-1-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(7,8-dihydro-6H-cyclopenta[g]quinoxalin-7-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chloro-1-methyl-1H-indol-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-pyrrolidin-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5,7-dichlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(3-pyridin-2-yl)phenyl)butanamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-3-(naphthalen-2-yl)propanamide;2-(5,6-dichlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(4,5-dichlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-3-(3-(pyridin-2-yl)phenyl)propanamide;N-((1R,2R)-1-(2,3-dhydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-fluoro-2,3-dihydro-1H-inden-2-yl)acetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4(naphthalen-2-yl)butanamide;N-((1S,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide;2-(benzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-fluorobenzofuran-2-yl)acetamide;(E)-4-(4-chlorophenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluorobut-3-enamide;N-((1R,2R)-3-(3-amino-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propen-2-yl-2,2-difluoro-2-(5-fluorobenzo[b]thiophen-2-yl)acetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(trifluoromethyl)benzofuran-2-yl)acetamide;2-(5-bromobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1S,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-3-(azetidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(quinolin-6-yl)propan-2-yl)acetamide;2-(S-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(quinolin-6-yl)propan-2-yl)acetamide;2-(S-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3,3-dimethylpyrrolidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-((S)-3-fluoropyrrolidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-((R)-2-methylpyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-((S)-2-methylpyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-3-(3,3-difluoropyrrolidin-1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(3-chloro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(2-azaspiro[3.3]heptan-2-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1-(1-methyl-1H-indazol-5-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)acetamide;N-((1R,2R)-3-(2-azabicyclo[2.2.1]heptan-2-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-dichlorobenzofuran-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-3-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1-(1-methyl-1H-indazol-6-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1S,2R)-1-hydroxy-1-(1-methyl-1H-indazol-6-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1-(6-methoxypyridin-3-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;N-[2-(2H,3H-benzo[e]1,4-dioxan-6-yl)(1R)-2-hydroxy-1-(pyrrolidinylmethyl)ethyl]-2-(5-chlorobenzo[d]furan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-deutero-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-deutero-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(3-(difluoromethyl)-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(3-(difluoromethyl)-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-dideutero-acetamide;N-((1R,2R)-1-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3,3-dimethylazetidin-1-yl)-1-hydroxypropan-2-yl)-2,2-difluoroacetamide;2-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;N-((1R,2R)-1-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(3-methylazetidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(5-chlorobenzofuran-2-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1S,2R)-1-(5-chlorobenzofuran-2-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;(E)-2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(5-(pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)acetamide;and2-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;2-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1l-yl)propan-2-yl)-2-oxoacetamide;2-(benzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;N-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide;N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-4-(naphthalen-2-yl)butanamide;2-(5-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;2-(4-(5-chlorothiophen-2-yl)phenyl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;2-(4-(5-chlorothiophen-2-yl)phenyl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-pyrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide;2-(4-(5-chlorothiophen-2-yl)phenyl)-2,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-ethynylphenyl)-2-oxoacetamide;4-(6-chloronaphthalen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluorobutanamide;2-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4-(difluoromethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide;2-(3-chloropyrrolo[1,2-b]pyridazin-6-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(7-chloroimidazo[1,2-a]pyridin-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(6-(trifluoromethyl)furo[3,2-c]pyridin-2-yl)acetamide;2-(6-chlorofuro[3,2-b]pyridin-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(2-(trifluoromethyl)furo[2,3-d]pyrimidin-6-yl)acetamide;2-(5-chlorothieno[3,2-b]furan-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorothieno[2,3-d]oxazol-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(2-chlorofuro[2,3-d]thiazol-5-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;3-(3-chlorobenzyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluorobut-3-enamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(2,2,5,5-tetradeuteropyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;N-((1R,2R)-1-(3-chloro-4-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;2-(5-chloro-2,3-dihydro-H-inden-2-yl)-N-((1R,2R)-1-(3-chloro-4-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1-(4-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;N-((1R,2R)-1-(4-chloro-3-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2,2-difluoroacetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R)-1-hydroxy-1-(2-isopropoxypyridin-4-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;(A)-2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide;2-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;(E)-2-(5-chloro-2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)acetamide;2-(5-chlorobenzofuran-2-yl)-2,2-difluoro-N-((1R,2R-1-hydroxy-1-(6-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)4-(6-fluoronaphthalen-2-yl)-2-oxobutanamide;(E)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-(hydroxyimino)butanamide;N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(trifluoromethyl)benzofuran-2-yl)acetamide;(E)-N-((1R,2R)-1-(6-cyclopropoxypyridin-3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(hydroxyimino)-2-(5-trifluoromethyl)benzofuran-2-yl)acetamide;N-((1R,2R)-1-(6-cyclopropoxypyridin3-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(5-(trifluoromethyl)benzofuran-2-yl)acetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-formamido-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide; (E)-N-((1R,2R)-3-(azetidin1-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)-2-(5-chlorobenzofuran-2-yl)-2-hydroxyimino)acetamide;2-(5-chlorobenzofuran-2-yl)-N-((1R,2R)-1-(3,5-dichloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoroacetamide;(E)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(6-fluoronaphthalen-2-yl)-2-(methoxyimino)butanamide;N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-((1-methyl-1H-indazol-6-yl)oxy)phenyl)-2-oxoacetamide;N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4-fluorophenyl)-1H-imidazol-4-yl)-2-oxoacetamide;2-(1-(6-chloronaphthalen-2-yl)-1H-pyrazol-3-yl)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;2-(1-(6-chloronaphthalen-2-yl)-1H-pyrazol-4-yl)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-oxoacetamide;2-((6-chloronaphthalen-2-yl)-1-methyl-1H-imidazol-2-yl)-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrolidin-1-yl)propan-2-yl)-2-oxoacetamide;N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(4-fluorophenyl)-1-methyl-1H-imidazol-2-yl)-2-oxoacetamide;N-((1R,2R,3S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)butan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide;N-((1R,2R)-1-(3-chlor-4-(difluoromethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(6-chlorobenzo[b]thiophen-2-yl)-2-oxoacetamide;2-(6-chlorobenzo[b]thiophen-2-yl)-N-((1R,2R)-1-(4′-fluoro-[1,1′-biphenyl]-4-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide;andN-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(2-oxopyrrolidin-1-yl)propan-2-yl)-2-(4′-fluoro-[1,1′-biphenyl]-4-yl)-2-oxoacetamide;and optionally as a tautomer, a single stereoisomer or mixture ofstereoisomers thereof and additionally optionally as a pharmaceuticallyacceptable salt thereof.
 30. A pharmaceutical composition, comprising:i) a compound of claim 1 optionally as a tautomer, a single stereoisomeror mixture of stereoisomers thereof and additionally optionally as apharmaceutically acceptable salt thereof, and ii) a pharmaceuticallyacceptable excipient or pharmaceutically acceptable carrier.
 31. Amethod of treating a disease or disorder, comprising administering acompound according to claim 1, wherein the disease or disorder is aglycolipid storage disease; a disease associated with glycolipidaccumulation; a disease that causes renal hypertrophy or hyperplasia; adisease that causes hyperglycemia or hyperinsulemia; a cancer in whichglycolipid synthesis is abnormal; an infectious disease caused byorganisms which use cell surface glycolipids as receptors or in whichsynthesis of glucosylceramide is essential or important;atherosclerosis; polycystic kidney disease; renal hypertrophy; diabetesmellitus; breast cancer, renal adenocarcinoma; brain cancer;neuroblastoma; lung cancer, intestinal cancer, pancreatic cancer;prostate cancer; a neuronal disorder, a neuronal injury; an inflammatorydisease or disorder, obesity; or Parkinson's disease.
 32. The method ofclaim 31, wherein the disease or disorder is Tay Sachs, Sandhoffs, GM1gangliosidosis, Fabry disease, or Gaucher disease.